CT of the Heart Principles and Applications

CT OF THE HEART

CONTEMPORARY CARDIOLOGY CHRISTOPHER P. CANNON, MD SERIES EDITOR CT of the Heart: Principles and Applications, edited by U. Joseph Schoepf, MD, 2005 Principles of Molecular Cardiology, edited by Marschall S. Runge, MD and Cam Patterson, MD, 2005 Heart Disease Diagnosis and Therapy: A Practical Approach, Second Edition, edited by Gabriel M. Khan, MD, FRCP, FRCP (C), FACC, 2005 Cardiovascular Genomics: Gene Mining for Pharmacogenomics and Gene Therapy, edited by Mohan K. Raizada, PhD, Julian F. R. Paton, PhD, Michael J. Katovich, PhD, and Sergey Kasparov, MD, PhD, 2005 Surgical Management of Congestive Heart Failure, edited by James C. Fang, MD and Gregory S. Couper, MD, 2005 Cardiopulmonary Resuscitation, edited by Joseph P. Ornato, MD, FACP, FACC, FACEP and Mary Ann Peberdy, MD, FACC, 2005 Cardiac Transplantation: The Columbia University Medical Center/New York-Presbyterian Hospital Manual, edited by Niloo M. Edwards, MD, Jonathan M. Chen, MD, and Pamela A. Mazzeo, 2004 Heart Disease and Erectile Dysfunction, edited by Robert A. Kloner, MD, PhD, 2004 Coronary Disease in Women: Evidence-Based Diagnosis and Treatment, edited by Leslee J. Shaw, PhD and Rita F. Redberg, MD, FACC, 2004 Complementary and Alternative Cardiovascular Medicine, edited by Richard A. Stein, MD and Mehmet C. Oz, MD, 2004 Nuclear Cardiology, The Basics: How to Set Up and Maintain a Laboratory, by Frans J. Th. Wackers, MD, PhD, Wendy Bruni, BS, CNMT, and Barry L. Zaret, MD, 2004 Minimally Invasive Cardiac Surgery, Second Edition, edited by Daniel J. Goldstein, md, and Mehmet C. Oz, MD 2004 Cardiovascular Health Care Economics, edited by William S. Weintraub, MD, 2003

Platelet Glycoprotein IIb/IIIa Inhibitors in Cardiovascular Disease, Second Edition, edited by A. Michael Lincoff, MD, 2003 Heart Failure: A Clinician’s Guide to Ambulatory Diagnosis and Treatment, edited by Mariell L. Jessup, MD and Evan Loh, MD, 2003 Management of Acute Coronary Syndromes, Second Edition, edited by Christopher P. Cannon, MD 2003 Aging, Heart Disease, and Its Management: Facts and Controversies, edited by Niloo M. Edwards, MD, Mathew S. Maurer, MD, and Rachel B. Wellner, MPH, 2003 Peripheral Arterial Disease: Diagnosis and Treatment, edited by Jay D. Coffman, MD and Robert T. Eberhardt, MD, 2003 Cardiac Repolarization: Bridging Basic and Clinical Science, edited by Ihor Gussak, MD, phd, Charles Antzelevitch, phd, Stephen C. Hammill, MD, Win K. Shen, MD, and Preben Bjerregaard, MD, DMSC, 2003 Essentials of Bedside Cardiology: With a Complete Course in Heart Sounds and Murmurs on CD, Second Edition, by Jules Constant, MD, 2003 Primary Angioplasty in Acute Myocardial Infarction, edited by James E. Tcheng, MD, 2002 Cardiogenic Shock: Diagnosis and Treatment, edited by David Hasdai, MD, Peter B. Berger, MD, Alexander Battler, MD, and David R. Holmes, Jr., MD, 2002 Management of Cardiac Arrhythmias, edited by Leonard I. Ganz, MD, 2002 Diabetes and Cardiovascular Disease, edited by Michael T. Johnstone, md and Aristidis Veves, MD, DSC, 2001 Blood Pressure Monitoring in Cardiovascular Medicine and Therapeutics, edited by William B. White, MD, 2001 Vascular Disease and Injury: Preclinical Research, edited by Daniel I. Simon, MD, and Campbell Rogers, MD, 2001 Preventive Cardiology: Strategies for the Prevention and Treatment of Coronary Artery Disease, edited by JoAnne Micale Foody, MD, 2001

CT OF THE HEART PRINCIPLES AND APPLICATIONS

EDITED BY

U. JOSEPH SCHOEPF, MD DEPARTMENT OF RADIOLOGY, MEDICAL UNIVERSITY OF SOUTH CAROLINA, CHARLESTON, SC

FOREWORD BY ALEXANDER R. MARGULIS, MD, DSC (HON) CLINICAL PROFESSOR OF RADIOLOGY, WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY, NEW YORK, NY

© 2005 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 www.humanapress.com For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel.: 973-256-1699; Fax: 973-256-8341; E-mail:[email protected]; Website: humanapress.com All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, Microfilming, recording, or otherwise without written permission from the Publisher. All articles, comments, opinions, conclusions, or recommendations are those of the author(s), and do not necessarily reflect the views of the publisher. Due diligence has been taken by the publishers, editors, and authors of this book to ensure the accuracy of the information published and to describe generally accepted practices. The contributors herein have carefully checked to ensure that the drug selections and dosages set forth in this text are accurate in accord with the standards accepted at the time of publication. Notwithstanding, as new research, changes in government regulations, and knowledge from clinical experience relating to drug therapy and drug reactions constantly occurs, the reader is advised to check the product information provided by the manufacturer of each drug for any change in dosages or for additional warnings and contraindications. This is of utmost importance when the recommended drug herein is a new or infrequently used drug. It is the responsibility of the health care provider to ascertain the Food and Drug Administration status of each drug or device used in their clinical practice. The publisher, editors, and authors are not responsible for errors or omissions or for any consequences from the application of the information presented in this book and make no warranty, express or implied, with respect to the contents in this publication. Cover illustration: figure 6D from chapter 25, “CT Angiography for Assessment of Coronary Artery Anomalies,” by Steffen C. Froehner, Matthias Wagner, Juergen Brunn, and Rainer R. Schmitt; figures 13 and 14 from chapter 3, “Scan Techniques for Cardiac and Coronary Artery Imaging With Multislice CT,” by Bernd M. Ohnesorge, Brian R. Westerman, and U. Joseph Schoepf; figure 13 from chapter 4, “Image Reconstruction for ECG-Triggered and ECG-Gated Multislice CT,” by Thomas Flohr and Tinsu Pan; figure 13 from chapter 24, “Visualization Techniques for Contrast-Enhanced CT Angiography of Coronary Arteries,” by JeanLouis Sablayrolles and Pascal Giat; and figure 9 from chapter 18, “Multidetector-Row CT Assessment of Left-Ventricular Function,” by Kai Uwe Juergens and Roman Fischbach. Production Editor: Tracy Catanese Cover design by Patricia F. Cleary This publication is printed on acid-free paper. ∞ ANSI Z39.48-1984 (American National Standards Institute) Permanence of Paper for Printed Library Materials. Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Humana Press Inc., provided that the base fee of US $25.00 per copy is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to Humana Press Inc. The fee code for users of the Transactional Reporting Service is: [1-58829-303-3/05 $25.00]. e-ISBN: 1-59259-818-8 Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1 Library of Congress Cataloging-in-Publication Data CT of the heart : principles and applications / edited by U. Joseph Schoepf. p. ; cm. -- (Contemporary cardiology) Includes bibliographical references and index. ISBN 1-58829-303-3 (alk. paper) 1. Heart--Tomography. [DNLM: 1. Heart--radiography. 2. Tomography, X-Ray Computed. WG 141.5.T6 C959 2004] I. Schoepf, U. J. (U. Joseph), 1969- II. Series: Contemporary cardiology (Totowa, N.J. : Unnumbered) RC683.5.T66C785 2004 616.1'20757--dc22 2004003443

Foreword

Radiologic technology has made dramatic advances in the last 25 years, and none have been more impressive than those in computed tomography (CT). The progress in the speed of obtaining images, computing, postprocessing, and spatial resolution has been incredible. The result is that CT has moved from displaying purely morphologic information to providing valuable physiologic data as well. Whether with electron beam or multidetector-row CT, advances are impressive and nowhere have the applications been more useful and dramatic than in the heart. This multiauthored book, CT of the Heart, edited by U. Joseph Schoepf, MD, is a splendid rendition of the state-ofthe-art in CT imaging of the heart; however, where appropriate, it also features comparisons with other technical approaches, such as magnetic resonance and ultrasound. The contributors are leading radiologists, cardiologists, physicists, engineers, and basic and clinical scientists from Europe, the United States, Israel, and Japan.

The entire contents are meticulous and comprehensive, from the introduction about the past, present, and future of CT of the heart, through the technical underpinning of the method and the various clinical, physiologic, and pathologic applications of CT in studying the heart. This book fills an immense need, particularly at a time when cardiac screening with CT, whether one agrees with this practice or not, is a reality. Furthermore, with the rapid increase of aging populations in the industrialized world, noninvasive diagnostic approaches are increasingly needed. As technology continues to advance and applications of CT to heart studies expand, it is my hope that the editor will bring this book up to date with a new edition. Alexander R. Margulis, MD, DSc (HON) Clinical Professor of Radiology Weill Medical College of Cornell University

v

Preface

ease burden is a promising and exciting but yet untested concept. Within CT of the Heart, the reader will be exposed to a variety of expert opinions on the respective topics. Some authors will assume a more optimistic or a more conservative perspective on cardiac CT applications. Because of the lack of large-scale clinical studies, only future experience will show who may be right. It is a declared goal of this book to showcase the full scope of current developments, research, and scientific controversy regarding the principles and applications of CT of the heart. Truth is most likely to be found in the equilibrium of opinions. The publisher and I have striven to maintain this equilibrium by providing a platform for differing opinions and for different technical approaches to CT of the heart. To mitigate commercial overtones and bias, which so often accompany the first steps of a potentially important new technology, contributions of users and/or developers of all cardiac CT manufacturers were included. Scientists representing different companies graciously disregarded commercial divisions and agreed to co-author chapters in order to provide the reader with a truly balanced view on cardiac CT technology. Accordingly, CT of the Heart is the work of many. I am indebted to Dr. Christopher Cannon, the series editor, and to Paul Dolgert of Humana Press for entrusting me with the role of editor. I am grateful to my chairman, Dr. Philip Costello, for his unfailing guidance, support, and friendship. I feel very, very honored by all the kindness that my many friends in the cardiac imaging community have shown me by volunteering their time, their knowledge, their experience, and the vision that went into their respective contributions. All authors are highly respected experts in their fields and this book would never have come to pass without their incredible support, for which I am so grateful. Finally I would like to thank Tracy Catanese and Craig Adams of Humana Press for so efficiently and expertly steering the production of CT of the Heart.

Through the ages of exploration and enlightenment the heart has kept its fascination as the metaphor of life. Its firm entrenchment in human emotion and consciousness and the overwhelming socioeconomic importance of its diseases make noninvasive visualization and diagnosis of the heart and its diseases the coveted “holy grail” of medical imaging. Imaging of the heart has always been technically challenging, because of the heart’s continuous motion. The introduction and ongoing technical improvement of fast ECG-synchronized computed tomography (CT) scanning of the heart has enabled imaging of the elusive but cardinal cardiac anatomy and pathology with a combination of speed and spatial resolution that is hitherto unparalleled by other noninvasive imaging modalities. Accordingly, considerable interest has been directed in recent years at the beneficial utilization of CT for noninvasive interrogation of the coronary arteries and for imaging studies of anatomic and functional sequelae of ischemic heart disease, such as cardiac perfusion, motion, and viability. The current and potential future roles of CT for these and other applications are the subject matter of this book. CT of the Heart, however, does not claim to have all of the answers. CT of the heart is a nascent but rapidly evolving field, and the act of condensing expert knowledge and experience in the format of a book can only result in a snapshot of the status quo at a certain point in time. Novel iterations of existing technology and profoundly new concepts of medical imaging are already on the horizon. The benefits and indications of integrating CT into the diagnostic algorithm of heart disease is intensely researched and discussed: to date, the diagnostic value of CT coronary calcium measurements and the exact role of this marker for cardiac risk stratification remain unclear and controversial. We are only beginning to understand the usefulness and potential clinical application of CT angiography for noninvasive detection of coronary artery stenosis. Cross-sectional assessment of the coronary artery wall for noninvasive identification, characterization, and quantification of atherosclerotic lesions and dis-

U. Joseph Schoepf, MD Charleston, South Carolina vii

Contents

FOREWORD ..................................................................... v PREFACE ...................................................................... vii CONTRIBUTORS ............................................................. xi

PART I 1

9

Axel Schmermund, Stefan Möhlenkamp, and Raimund Erbel

INTRODUCTION AND HISTORICAL BACKGROUND

William Stanford

2

10

Detection and Quantification of Coronary Calcium With Dual-Slice CT ........................ 91

11

Detection and Quantification of Calcified Coronary Plaque With Multidetector-Row CT........................ 101

Joseph Shemesh

CT of the Heart: Past, Present, and Future ......... 3

PART II

TECHNICAL BACKGROUND

J. Jeffrey Carr

Electron Beam CT of the Heart ......................... 15

12

David G. Hill

3

Scan Techniques for Cardiac and Coronary Artery Imaging With Multislice CT .............. 23

Image Reconstruction for ECG-Triggered and ECG-Gated Multislice CT ...................... 45

5

Phase-Correlated Image Reconstruction Without ECG .................................................. 55

13

Thomas Flohr and Tinsu Pan

Noninvasive Quantification of Coronary Calcium: Quantification Methods, Scanner Types, Scan Protocols, Accuracy, and Reproducibility .................... 129 Stefan Ulzheimer, Kaiss Shanneik, and Willi A. Kalender

PART IV CONTRAST-ENHANCED CT OF THE HEART: MORPHOLOGY AND FUNCTION

Marc Kachelriess and Willi A. Kalender

6

Coronary Calcium Scoring With Multidetector-Row CT: Rationale and Scoring Techniques .............. 111 Roman Fischbach and David Maintz

Bernd M. Ohnesorge, Brian R. Westerman, and U. Joseph Schoepf

4

Detection and Quantification of Coronary Calcium With Electron Beam CT .................. 83

Radiation Dose From CT of the Heart ............... 63

14

Cynthia H. McCollough

CT of the Pericardium ...................................... 145 Reinhard Groell

PART III DETECTION AND QUANTIFICATION OF CORONARY CALCIUM 7

15

Jürgen K. Willmann and Dominik Weishaupt

Coronary Calcium Screening: An Epidemiologic Perspective ....................... 71

16

Christopher J. O’Donnell and Udo Hoffmann

8

Multidetector-Row CT for Assessment of Cardiac Valves ......................................... 155 Multislice CT of the Heart and Great Vessels in Congenital Heart Disease Patients .......... 161 Jean-François Paul

Coronary Calcium Scanning: Why We Should Perform It ............................ 79

17

Axel Schmermund, Stefan Möhlenkamp, and Raimund Erbel

Imaging of Cardiac and Paracardiac Masses and Pseudotumors ........................................ 171 Bernd J. Wintersperger

ix

x

18

CONTENTS

Multidetector-Row CT Assessment of Left-Ventricular Function ....................... 183

29

Kai Uwe Juergens and Roman Fischbach

19

20

Imaging Intramyocardial Microcirculatory Function Using Fast Computed Tomography ................................................. 195

Heiko Pump, Stefan Möhlenkamp, Raimund Erbel, and Rainer Seibel

Stefan Möhlenkamp, Axel Schmermund, Birgit Kantor, Raimund Erbel, and Erik L. Ritman

30

Approaches for Assessing Myocardial Viability With Multidetector-Row CT ........ 207

31

21

CONTRAST-ENHANCED CT OF THE HEART: CORONARY ARTERIES

Anatomy of the Coronary Arteries and Veins in CT Imaging ............................. 219 Robert J. M. van Geuns and Filippo Cademartiri

22

Techniques and Protocols for Acquisition and Display of Contrast-Enhanced CT Angiography ................................................. 229 Contrast Material Injection Techniques for CT Angiography of the Coronary Arteries .......... 237

32

Visualization Techniques for ContrastEnhanced CT Angiography of Coronary Arteries .................................... 247

PART VI CONTRAST-ENHANCED CT OF THE HEART: PRINCIPLES OF ATHEROSCLEROSIS AND VESSEL WALL IMAGING 33

CT Angiography for Assessment of Coronary Artery Anomalies .......................................... 259

34

Multidetector-Row CT for Assessment of Kawasaki Disease .................................... 279

35

Multidetector-Row CT of the Coronary Arteries for Planning of Minimally Invasive Bypass Surgery .............................. 287 Christopher Herzog, Selami Dogan, and Thomas J. Vogl

28

CT Angiography for Assessment of Coronary Bypass Grafts .................................................. 301 Marcello De Santis

Multidetector-Row CT Imaging of Clinical and Preclinical Coronary Atherosclerosis ... 377 Christoph R. Becker

36

Multidetector-Row CT vs Intravascular Ultrasound for Coronary Plaque Characterization ........................................... 381

37

Multidetector-Row CT vs Magnetic Resonance Imaging for Coronary Plaque Characterization ............................... 389

Axel Kuettner

Toru Sakuma and Kunihiko Fukuda

27

Pathogenesis of the Vulnerable Atherosclerotic Plaque ................................. 365 Masanori Aikawa

Steffen C. Froehner, Matthias Wagner, Juergen Brunn, and Rainer R. Schmitt

26

Pathology and Pathophysiology of Coronary Atherosclerotic Plaques ............................... 351 Renu Virmani, Allen P. Burke, Frank D. Kolodgie, Andrew Farb, Aloke V. Finn, and Herman Gold

Jean-Louis Sablayrolles and Pascal Giat

25

CT vs Magnetic Resonance for Imaging of the Coronary Arteries .............................. 339 Armin Huber

Filippo Cademartiri and Koen Nieman

24

Complementary Use of Coronary Calcium Scoring and CT Angiography ...................... 333 Alexander W. Leber

Christoph R. Becker

23

CT Angiography for the Detection of Coronary Artery Stenosis ........................ 321 Koen Nieman and Filippo Cademartiri

Yasushi Koyama and Teruhito Mochizuki

PART V

Contrast-Enhanced Electron Beam CT and Multidetector-Row CT in the Evaluation of Coronary Stent Patency ................................................ 311

Konstantin Nikolaou, Christoph R. Becker, and Zahi Fayad

38

Multidetector-Row CT for Detection of Noncalcified and Calcified Coronary Lesions: Clinical Significance ..................... 399 Stephen Schroeder

INDEX ......................................................................... 401

Contributors

MASANORI AIKAWA, MD, PhD, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA CHRISTOPH R. BECKER, MD, Department of Clinical Radiology, University of Munich, Munich, Germany JUERGEN BRUNN, MD, Department of Diagnostic and Interventional Radiology, Herz- und Gefaess-Klinik GmbH, Bad Neustadt an der Saale, Germany ALLEN P. BURKE, MD, Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC FILIPPO CADEMARTIRI, MD, Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands J. JEFFREY CARR, MD, MSCE, Division of Radiological Sciences and Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC MARCELLO DE SANTIS, MD, Department of Radiology, S. Andrea Hospital, Rome, Italy SELAMI DOGAN, MD, Department of Thoracic and Cardiovascular Surgery, J. W. Goethe University, Frankfurt, Germany RAIMUND ERBEL, MD, Department of Cardiology, University Clinic Essen, Essen, Germany ANDREW FARB, MD, Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC ZAHI FAYAD, MD, Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY ROMAN FISCHBACH, MD, Department of Clinical Radiology, University of Muenster, Muenster, Germany ALOKE V. FINN, MD, Cardiac Unit, Department of Internal Medicine, Massachusetts General Hospital, Boston, MA THOMAS FLOHR, Division of Computed Tomography, Siemens Medical Solutions, Forchheim, Germany

STEFFEN C. FROEHNER, MD, Department of Diagnostic and Interventional Radiology, Herz- und Gefaess-Klinik GmbH, Bad Neustadt an der Saale, Germany KUNIHIKO FUKUDA, MD, Department of Radiology, The Jikei University School of Medicine, Tokyo, Japan PASCAL GIAT, PhD, Division of Computed Tomography, General Electric Medical Systems, Buc, France HERMAN GOLD, MD, Cardiac Unit, Department of Internal Medicine, Massachusetts General Hospital, Boston, MA REINHARD GROELL, MD, Department of Radiology, Medical University Graz, Graz, Austria CHRISTOPHER HERZOG, MD, Institute for Diagnostic and Interventional Radiology, J. W. Goethe University, Frankfurt, Germany DAVID G. HILL, PhD, General Electric Medical Systems, South San Francisco, CA UDO HOFFMANN, MD, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA ARMIN HUBER, MD, Department of Clinical Radiology, University of Munich, Munich, Germany KAI UWE JUERGENS, MD, Department of Clinical Radiology, University of Muenster, Muenster, Germany MARC KACHELRIESS, PhD, Institute of Medical Physics, University of Erlangen-Nürnberg, Nürnberg, Germany WILLI A. KALENDER, PhD, Institute of Medical Physics, University of Erlangen-Nürnberg, Nürnberg, Germany BIRGIT KANTOR, MD, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN FRANK D. KOLODGIE, PhD, Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC xi

xii

YASUSHI KOYAMA, MD, Department of Cardiology, Ehime Prefectural Imabari Hospital, Ehime, Japan AXEL KUETTNER, MD, Department of Radiology, University of Tübingen, Tübingen, Germany ALEXANDER W. LEBER, MD, Medizinische Klinik I, University Hospital Clinic Munich-Grosshadern, Ludwig Maximilians University, Munich, Germany CYNTHIA H. MCCOLLOUGH, PhD, Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN DAVID MAINTZ, MD, Department of Clinical Radiology, University of Muenster, Muenster, Germany ALEXANDER R. MARGULIS, MD, DSc (HON), Department of Radiology, Weill Medical College of Cornell University, New York, NY TERUHITO MOCHIZUKI, MD, Department of Radiology, Ehime University School of Medicine, Ehime, Japan STEFAN MÖHLENKAMP, MD, Department of Cardiology, University Clinic Essen, Essen, Germany KOEN NIEMAN, MD, Department of Cardiology (Thoraxcenter) and Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands KONSTANTIN NIKOLAOU, MD, Department of Clinical Radiology, University of Munich, Munich, Germany, and Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY CHRISTOPHER J. O’DONNELL, MD, MPH, National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA, and Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA BERND M. OHNESORGE, PhD, Division of Computed Tomography, Siemens Medical Solutions, Forchheim, Germany TINSU PAN, General Electric Medical Systems, Waukesha, WI JEAN-FRANÇOIS PAUL, MD, Radiology Unit, Marie Lannelongue Hospital, Plessis Robinson, France HEIKO PUMP, MD, Institute of Diagnostic and Interventional Radiology, University of WittenHerdecke, Witten-Herdecke, Germany ERIK L. RITMAN, MD, PhD Physiological Imaging Research Laboratory, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN JEAN-LOUIS SABLAYROLLES, MD, Centre Cardiologique du Nord, Saint Denis, France

CONTRIBUTORS

TORU SAKUMA, MD, Department of Radiology, The Jikei University School of Medicine, Tokyo, Japan AXEL SCHMERMUND, MD, Department of Cardiology, University Clinic Essen, Essen, Germany RAINER R. SCHMITT, MD, Department of Diagnostic and Interventional Radiology, Herz- und GefaessKlinik GmbH, Bad Neustadt an der Saale, Germany U. JOSEPH SCHOEPF, MD, Department of Radiology, Medical University of South Carolina, Charleston, SC STEPHEN SCHROEDER, MD, PhD • Division of Cardiology, Eberhard-Karls-Universität, Tübingen, Germany RAINER SEIBEL, MD, Institute of Diagnostic and Interventional Radiology, University of WittenHerdecke, Witten-Herdecke, Germany KAISS SHANNEIK, MSc, Institute of Medical Physics, University of Erlangen-Nürnberg, Nürnberg, Germany JOSEPH SHEMESH, MD, Department of Cardiology, The Grace Ballas Cardiac Research Unit, Sheba Medical Center, Sackler School of Medicine, Tel Aviv, Israel WILLIAM STANFORD, MD, Division of Chest and Cardiovascular Radiology, Department of Radiology, Ray J. and Lucille A. Carver University of Iowa College of Medicine, Iowa City, IA STEFAN ULZHEIMER, PhD, Division of Computed Tomography, Siemens Medical Solutions, Forchheim, Germany ROBERT J. M. VAN GEUNS, MD, Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands RENU VIRMANI, MD, Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC THOMAS J. VOGL, MD, Institute for Diagnostic and Interventional Radiology, J. W. Goethe University, Frankfurt, Germany MATTHIAS WAGNER, MD, Department of Diagnostic and Interventional Radiology, Herz- und GefaessKlinik GmbH, Bad Neustadt an der Saale, Germany DOMINIK WEISHAUPT, MD, Institute of Diagnostic Radiology, University Hospital Zurich, Zurich, Switzerland BRIAN R. WESTERMAN, PhD, Division of Computed Tomography, Toshiba Medical Solutions, Los Angeles, CA JÜRGEN K. WILLMANN, MD, Institute of Diagnostic Radiology, University Hospital Zurich, Zurich, Switzerland BERND J. WINTERSPERGER, MD, Department of Clinical Radiology, University of Munich, Munich, Germany

CHAPTER 1 / PAST, PRESENT, FUTURE OF CT

1

INTRODUCTION I AND HISTORICAL BACKGROUND

CHAPTER 1 / PAST, PRESENT, FUTURE OF CT

1

3

CT of the Heart Past, Present, and Future WILLIAM STANFORD, MD

INTRODUCTION

patient was scanned (Fig. 2A). Scan times of 4.5 min per image were required. The technology was then advanced with the addition of fan beam architecture to the translate/rotate process. With this refinement, each radiation beam activated multiple detectors rather than a single detector. Thus increased numbers of images were possible from each tube activation. With this upgrade, imaging times were reduced to approx 2.5 min per image (Fig. 2B). The next advance was the introduction of a continuously rotating X-ray tube coupled with a continuously rotating detector array. This further decreased scan times to approx 18 s (Fig. 2C). Around 1978, the rotating detector array concept was changed to that of a fixed detector array, and this further decreased scan times to approx 2 s per image, and this is the configuration present in many of our conventional CT scanners in operation today (Fig. 2D). As a consequence of these advances, CT was able to become a major workhorse for whole-body imaging, which included many cardiac applications. However, although the excellent resolution and absence of overlying structures allowed visualization of the pericardium and many of the relatively static abnormalities such as intracardiac filling defects from thrombi and tumors, the contracting heart was not well visualized. An additional problem with this conventional technology was that the scanner cabling restricted tube movement and allowed for only a single tube rotation to a fixed point before the tube had to be returned to its original position. Thus a continuous tube movement was not possible and scan times were relatively fixed. Because of this, cardiac applications were restricted to a 2-s-per-image acquisition time. Yet, the ability to visualize not only the vessel lumina and cardiac chamber endocardium but also the vessel wall and the surrounding myocardium were important applications not heretofore possible. Thus CT provided a more comprehensive view of cardiovascular pathology. In the early 1980s, an important advance moved CT into the realm of cardiac imaging. This was the introduction of the electron beam technology concept by Dr. Douglas Boyd of the University of California, San Francisco (3). The electron beam scanner, while having an appearance similar to a conventional CT scanner, did not have an X-ray tube rotating around the patient. Instead, electrons were generated by a source and then

Imaging of the heart and great vessels has previously been done with plain film, cardiac catheterization, nuclear medicine, and echocardiography as the primary imaging modalities. The recent newer advances in the computed tomography (CT) and magnetic resonance imaging (MRI) technologies, however, have dramatically changed our approach to imaging cardiac disease. CT and MRI, supplemented by CT angiography and MRI angiography, are increasingly replacing the chest film, as well as nuclear and—to some extent—echo imaging as the primary modalities in evaluating heart disease. CT images, which initially took over 4 min to generate, can now be obtained in 50–100 ms with electron beam imaging and in 125–500 ms with helical imaging. Importantly, these advances in temporal resolution are rapid enough to essentially stop cardiac motion, and thus visualization of extremely small structures such as calcium deposits within the walls of the coronary arteries is now possible. Along with this increased temporal resolution has come a concomitant increase in spatial resolution, and isotropic voxels as small as 0.5 mm3 are now identifiable. These advances, along with the increasing use of 3D reconstruction techniques, have revolutionized cardiac imaging and have moved CT from only anatomic visualization into the arena of functional and perfusion imaging.

HISTORICAL CT was first introduced by Sir Godfrey Hounsfield in the 1970s—a short 30 yr ago (1,2) (Fig. 1). Hounsfield was an electrical engineer working for EMI, an electronics firm in England. While there, he conceived the idea of taking crosssectional X-ray data and reformatting these data into images. For this, he and Alan M. Cormack, a Tufts professor of mathematics working independently, received the Nobel Prize in medicine in 1979. Hounsfield’s first-generation scanner used a translate/rotate technology. In this methodology, an X-ray source moving laterally activated a series of single detectors before moving to another position and repeating the process. This translate/rotate process was repeated until the entire circumference of the From: Contemporary Cardiology: CT of the Heart: Principles and Applications Edited by: U. Joseph Schoepf © Humana Press, Inc., Totowa, NJ

3

4

STANFORD

Fig. 1. Godfrey N. Hounsfield, the father of computed tomography. For their achievements, Hounsfield and Alan M. Cormack were awarded the Nobel Prize in medicine in 1979.

Fig. 2. (A) Diagram of the first-generation translate/rotate CT scanner. To create the image, a series of exposures were taken as the X-ray source moved a short distance laterally. The tube then rotated to a different position and the sequence was repeated. A single image required 4.5 min exposure time. (B) A later modification of the translate/rotate sequence introduced fan beam architecture to activate multiple detectors before moving to a new position. With this modification, scan times were reduced to 2.5 min/image. (C) The next generation of scanners used a rotating X-ray source coupled to rotating detectors. Scan times were reduced to 18 s/image. (D) Subsequent modifications used a rotating X-ray source with a fixed detector sarray. Scan times were 2 s/image.

CHAPTER 1 / PAST, PRESENT, FUTURE OF CT

5

Fig. 3. Cross-sectional diagram of the GE-Imatron C150 XP electron beam scanner. Electron sweeps of tungsten target rings generate X-rays that traverse the patient to activate detectors in the gantry over the patient. With this development, imaging times were reduced to 50–100 ms. (Courtesy GE-Imatron Inc.)

bent electromagnetically to sweep tungsten target rings located in the gantry beneath the patient. The X-rays produced by the electron sweep traversed the patient and were collected by fixed solid-state detectors located in the gantry above the patient (Fig. 3). This technology decreased scan times to 50–100 ms, which essentially froze cardiac motion and thus dramatically changed our ability to image the beating heart. For the first time it was possible to view cardiac contractions and to visualize small structures such as calcium deposits within the walls of the coronary artery. An additional major advance in CT imaging came in the early 1990s with the introduction of helical/spiral CT imaging and its slip-ring technology (4) (Fig. 4). With these advances, the X-ray beam was able to continuously rotate around the patient as the patient moved through the scanner gantry. These innovations decreased scan times to approx 500–1000 ms and ultimately produced data sets with spatial resolutions as small as 0.5 mm3. The initial platform for helical CT scanners consisted of a single X-ray source and a single detector ring; however, subsequent developments in helical CT technology have enlarged imaging platforms from a single detector to 4 rows and now 16 rows, and in the future 32-, 64-, and 256-row detectors are expected. Along with the increase in numbers of detector rows were advances in the temporal resolution, and now imaging times now as fast as 420 ms are possible. These and other innovations in multislice helical CT have allowed the entire heart to be scanned within a 20–30 s breath-hold, and do so with excellent spatial resolution (5).

THE PRESENT CONVENTIONAL CT

The design of our current conventional CT scanners is that of a rotating X-ray source activating fixed detectors in the gantry surrounding the patient. The tube movement is limited by cables so that once the tube rotates around the patient, it has to stop and rewind. This constrained tube travel is a major limitation of conventional CT; however, the cross-sectional image detail is excellent and spatial resolutions of 9–12 line pairs (lp)/ cm are possible. ELECTRON BEAM CT

The electron beam CT (EBCT) scanner (GE-Imatron) works on a different principle than does conventional CT. With EBCT, electrons sweep tungsten target rings to produce X-rays that enter from beneath the patient, and are attenuated and collected by solid-state detectors in the gantry above the patient. The technology, because of the absence of moving parts, dramatically decreases scan times to 50–100 ms, which is rapid enough to essentially freeze cardiac motion. There are several different EBCT scanner models in operation. The older C150 and C300 scanners operate at 130 kV, 625 mA, 83 kW to produce 100-ms, 1.5-, 3-, and 6-mm slice thickness images at resolutions of 9.5 lp/cm. The technology also makes it possible to generate flow and movie mode 50-ms, 8-mm dual slice thickness images from four target rings. The latter ability is important in functional imaging; its spatial resolution is limited at 4.5 lp/cm.

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Fig. 4. A modern helical CT imaging suite.

The newer EBCT e-Speed™ version operates at 140 kV, 1000 mA, 140 kW. It can generate dual 1.5-, 3-, and 8-mm slices, at 50 ms temporal resolution. The spatial resolution is 10 lp/cm. This version also has a 100-ms mode for higher spatial resolution and a 33-ms mode for higher temporal resolution. Both are significant advances in EBCT technology. Flow Mode

EBCT uses several sequences to image the heart. In the flow mode sequence, the C150 and C300 scanners generate eight 8-mm images in 224 ms. Then, following an 8-ms delay to reset the beam, an additional eight 8-mm slices can be generated in another 224 ms. The advantage of this configuration is that a stack of multilevel images can be obtained almost simultaneously, thus allowing visualization of a contrast bolus as it enters, peaks, and washes out of a region of interest (Fig. 5). This sequence is similar to the first-pass studies used in nuclear medicine. Flow mode sequences are useful in evaluating coronary artery bypass graft patency, intracardiac shunts, and arteriovenous malformations, as well as identifying bolus arrival times in aberrant vessels. Movie Mode

A more commonly used EBCT sequence is the movie (cine) sequence. In this configuration, the C150 and C300 scanners can generate images of the contracting heart every 58 ms (17 images per second). These images can be acquired during systole and diastole, which allows visualization during a cardiac contraction (Fig. 6). This sequence, usually consisting of

10–12 same-level images, is triggered off the R wave of the ECG. Once completed, it then takes 8 ms for the scanner to reset, and another 10–12 image data set at the same or usually a different level can be obtained. The spatial resolution in the flow and movie modes is moderate at 4.5 lp/cm; however, with the new e-Speed model, resolutions of 10 lp/cm are possible. Movie sequences are important in quantifying cardiac function and in evaluating abnormal contraction patterns, such as those seen post myocardial infarction. Also, by completely opacifying the cardiac chambers, filling defects such as thrombi or tumors are readily identified. Step Volume and Continuous Volume Scans

Lastly, in the step volume scan (SVS) and continuous volume scan (CVS) modes, 1.5-, 3-, or 6-mm single-slice thicknesses are obtainable. In the SVS sequence, the temporal resolution of the C150 and C300 platforms is 100 ms, which is 9 images per second, with the pixel sizes varying from 0.06 to 1 mm2. With the e-Speed, 50-ms volume scan sequences at 17 or 34 images per second are possible, depending upon whether one or two detectors are used. The SVS images can be triggered at preset intervals from the ECG signal. The maximal resolution is 10 lp/cm, depending upon the field of view and the reconstructive algorithm selected. In the SVS mode, images are acquired in a manner similar to that of conventional CT scanners—i.e., a single target ring is swept to produce an image and then the table moves and a second image is generated. Multiple sweeps of the same target can be taken and volume averaged if

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Fig. 5. An electron beam CT flow mode sequence showing a contrast bolus opacifying the right atrium and ventricle, and then washing out and later appearing in the left ventricle. This sequence is useful in evaluating bypass graft patency, intracardiac shunts, and arteriovenous malformations, as well as identifying contrast arrival in aberrant vessels.

additional resolution is required; however, this comes at the price of increased radiation exposure. The continuous volume mode (CVS) is similar to that of spiral or helical CT methodologies, with up to 140 images on the C150, up to 280 images on the C300, and 400 images on the e-Speed scanners possible during an acquisition period of about 33 s. The minimum exposure time is 100 ms (33 ms on e-Speed) and the images can be contiguous or overlapped. On the C150 or C300 scanners, this mode allows a complete 140-slice, 3mm thick data set to be acquired during a 17-second breathhold. Scan widths of 1.5–10 mm are possible. HELICAL CT

Current-generation helical/spiral CT scanners have multirow detectors capable of generating 1 to 16 slices of varying thickness with each gantry rotation. Technological advances have

reduced gantry rotation times from 1 s to 420 ms, and with segmented reconstruction, image times approximating 100 ms are possible. An additional advantage of the helical technology is that the detector information is generated as a volumetric data set, and this permits later reformations of different slice thickness that allows 3D reconstructions. Helical CT images are commonly ECG gated, and this further decreases motion artifacts by being able to restrict image acquisition to the quiet phase of the cardiac cycle. The latter is particularly important in coronary calcification screening. Helical/Spiral CT Sequence

In cardiac imaging, helical CT scanners are operated in two basic modes, both gated from the patient’s ECG. The first mode, designated prospective gated scanning, activates the X-ray tube for only the time needed to acquire a partial image. This is

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Fig. 7. Electron beam CT long axis (four-chamber) view image showing the left and right atria, left and right ventricles, and left-ventricular outflow tract.

Fig. 6. Electron-beam short axis movie mode images at the mid-leftventricular level in diastole (A) and systole (B). This sequence is useful in quantifying cardiac function and evaluating abnormalities of wall motion.

Retrospective gated scanning is the other operating mode of helical scanners. This sequence involves the helical scanning of the entire heart while at the same time recording the patient’s ECG. After the scan, images are reconstructed at a preselected phase of the cardiac cycle. This mode is commonly used for coronary artery angiography and for cardiac functional analysis. In order to avoid anatomical gaps in the data set, the helical pitch is set lower than that used for general body imaging. Thus the dose to the patient is higher. Nevertheless, the ability to reconstruct images in multiple phases from the same high-resolution data set can provide important information. Submillimeter slices, as small as 0.5 mm, can be used to achieve a high spatial resolution, and cardiac data collection can be accomplished in about 30 s. However, the patient’s heart rate is again a major factor in maintaining high image quality. If the heart rate exceeds 70 beats per minute (bpm), segmented image reconstruction can be used. This algorithm uses data from two, three, or four consecutive cardiac cycles to reconstruct a single image, thus improving the temporal resolution significantly and extending the range of heart rates that can be scanned with high-quality images.

ADDITIONAL CONSIDERATIONS IMPORTANCE OF TEMPORAL RESOLUTION

roughly half the gantry rotation time, or as short as 200–250 ms. The time of data collection is measured from the R wave, and the operator selects this delay. This mode is frequently used for coronary artery calcium imaging, because the radiation dose to the patient is kept to a minimum. However, rapid or irregular patient heart rates can affect image quality and the reproducibility of the study. Data collection periods that extend beyond diastole may exhibit motion artifacts that can reduce accuracy. A 4-detector ring scanner rotating at 0.5 s and programmed to provide 3-mm slices can acquire a data set in about 20 s, a reasonable breath-hold for most patients. Sixteen-row detector scanners in the same study reduced scanning times to roughly 8–12 s.

Although conventional, helical, and EBCT are able to identify cardiac anatomy, motion artifacts can still remain a problem. With contrast enhancement, conventional CT can image cardiac chambers and great vessel anatomy extremely well. However, helical/spiral CT and EBCT, because of their faster scan times, are suited better for imaging moving structures. In a typical cardiac sequence, the superior and inferior vena cavae, pulmonary arteries, and aorta are routinely visualized, as are the right and left atria and ventricles, and their outflow tracts (Fig. 7). With CT, the interfaces between the contrast-enhanced cardiac chambers and myocardium are usually well defined, especially if the image is acquired during diastole; in systole this interface may be partially degraded by motion. Overall, both helical/spiral CT and EBCT, because of their faster scan times, generally better define struc-

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Fig. 8. Heart model showing the cross-sectional planes used in cardiac imaging.

tural detail (5). Although it is important that the patient remain quiet and suspend respiration, often it is still possible with the EBCT and helical/spiral CT scanners to obtain satisfactory images, even if the individual is unable to hold his or her breath. CONTRAST CONSIDERATIONS

In cardiac imaging, contrast administration is often necessary. The contrast material is usually administered as a bolus or as a continuous infusion, but because of the speed of the scanners, contrast arrival times become critical. Commonly, volumes of 80–150 mL of contrast material, varying from 240 to 370 mg of iodine per mL, are administered. Generally, the contrast material is infused at a rate of 1–4 mL/s using a power injector. For contrast administration, timing methodologies become important to ensure contrast optimization. One method is to administer a test bolus of 10 mL of contrast material and perform repeated imaging over the area of interest to determine contrast bolus arrival time. Another is to perform a circulation time using either cardiogreen dye or a solution of 0.5% magnesium sulfate. Both are injected at approx 4 mL/s. With magnesium sulfate, approx 10 mL of 0.5% solution is commonly administered, with bolus arrival being manifested by a warm sensation in the back of the tongue or throat. With cardiogreen

dye, an earlobe densitometer records the arrival of the bolus. Other techniques are the “sure start” technologies, where the scanner monitors the rise in contrast attenuation over the area of interest. When the attenuation approaches the preselected threshold, the scanner is triggered automatically. Alternatively, a fixed delay of 15–30 s may be used. POSITIONAL CONSIDERATIONS

Cardiac CT scanning, especially in evaluating cardiac function, requires imaging in planes less familiar to radiologists. The oblique position of the heart requires modifications to our traditional scanning planes. The two configurations commonly used in cardiac imaging are the short axis view, wherein the ventricle is “bread-loafed” (Fig. 8), and the “four-chamber view,” which slices the heart longitudinally from top to bottom and produces images that are similar to those familiar to our echocardiology colleagues (Fig. 7). RADIATION DOSAGE

The effective dose is the overall radiation exposure to the patient. This is designated in mSv, and is frequently equated to months of background exposure. For an EBCT calcium study, the effective dose would be 1.0 mSv in males and 1.3 mSv in women (4.0 and 5.2 mo of background radiation, respectively) (6).

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Fig. 9. Electron beam CT image showing an apical thrombus in the tip of an akinetic left ventricle in a postmyocardial-infarction patient.

Fig. 10. Helical CT image of calcifications in the left anterior descending coronary artery.

For a multislice helical/spiral CT prospectively triggered coronary calcification study, the effective dose would be 1.5 mSv in males and 1.8 mSv in women (6 and 7.2 mo of background radiation). If a multislice helical/spiral CT coronary calcium study were retrospectively triggered, this would increase the radiation exposure to 3.0 mSv in males and 3.6 mSv in women, which would amount to 12 and 14.4 mo of background radiation (6). For a 50-ms EBCT cine sequence, the exposure would be 0.58 mSv per image; for a 10-image sequence, this would give an exposure of 5.8 mSv (23.2 mo of background exposure). One additional advantage of the electron beam technology is that the radiation beam enters from beneath the patient, which reduces exposure to breast and thyroid tissue. If a CT angiographic study were done using retrospective gating, the radiation dose could reach as high as 10.9 mSv in men and 13.0 mSv in women (43.6 and 52 mo) (6). However, tube current modulation techniques have now been introduced that can ramp down the power during noncritical times, and this can decrease radiation exposure by up to 80% (5). CARDIAC APPLICATIONS Both EBCT and helical/spiral CT are useful in defining cardiac and great vessel anatomy. The excellent spatial and temporal resolutions allow identification of intracardiac filling defects such as thrombi and tumors (7) (Fig. 9), and the identification of defects of the pericardium (8). Functional imaging can quantify stroke volumes and ejection fractions, as well as evaluate abnormalities of wall motion and perfusion, especially in postinfarct patients (9,10,11). More recently, imaging of coronary calcification (12,13,14) (Fig. 10) and CT angiography for identifying coronary stenoses (15,16,17) (Fig. 11) and soft, noncalcified coronary atherosclerotic plaque (18) (Fig. 12) have become extremely important applications.

have excellent temporal and spatial resolution; however, one must recognize that because some organs such as the heart do not lie in conventional imaging planes, true short and longitudinal axis anatomical images may not be possible without reformatting. To partially overcome this problem, some scanner couches and/or gantries can be tilted to position the heart into a more appropriate scanning plane. Generally, cardiac images are acquired in a short axis plane similar to “bread loafing,” or in the longitudinal axis projection similar to the “four-chamber view” of echocardiography (Fig. 8). Because of the excellent resolution of CT, imaging of structures as small as 0.5 mm is possible. Additionally, tissues with different CT attenuations, such as fat, myocardium, and calcium, can be readily identified. An example is in imaging of the pericardium, where the low-attenuation epicardial and mediastinal fat lie adjacent to the higher-attenuation, fibrous pericardium. Commonly, the addition of iodinated contrast material allows further definition of the myocardium, and functional imaging of the heart is possible.

ADVANTAGES OF CT The main advantage of CT imaging is that cross-sectional images without overlying structures are generated. The images

DISADVANTAGES OF CT The disadvantages of even the faster CT technologies are the still somewhat long scan times which, unfortunately, do not completely eliminate cardiac motion. Other disadvantages inherent in all scanners are that they are stationary and the patient has to be transported to the scanner and be subjected to radiation. Also, contrast administration is often necessary, and weight restrictions may prevent some patients being scanned.

THE FUTURE The ideal X-ray imaging system would be to combine the attributes of conventional radiography to produce images with spatial resolution in the order of 5 1p/mm and acquisition times of tens to hundredths ms that would be sufficient to freeze physiologic motion. In addition, the ideal system would respond linearly over a wide range, exclude scatter, and provide 3D

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Fig. 11. Electron beam CT shaded surface display image showing a stenosis in the left anterior descending coronary artery pre- (A) and post(B) balloon angioplasty. (Courtesy Moshage et al. [15].)

Fig. 12. Helical CT angiography image demonstrating areas of noncalcified plaque in the wall of an left anterior descending coronary artery.

information free of superimposing tissues with isotropic resolution throughout (19). Also, it would provide the ability to image in transverse sections and thus avoid the problem of superimposed tissues. CT still has a long way to go, but continued improvements in temporal and spatial resolution are

expected. Already, prototype platforms of 256 detector rows are being developed and tested. Isotropic voxel resolutions of 0.5 × 0.5 × 0.5 mm are now possible, and from these 3D data sets it is possible to replicate true anatomy. Sector reconstruction can decrease scan times to below 100 ms, and EBCT scan-

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ners that may reduce scan times to under 33 ms are under development. Techniques to decrease scatter and noise are being evaluated, and these should further improve image quality and decrease motion blur. These and other refinements have made possible functional and perfusion imaging. Thus, the future of CT imaging of the heart is very exciting, and expectations are that CT will play an ever-increasing role in cardiac imaging.

REFERENCES 1. Hounsfield GN. Computerized transverse axial scanning (tomography): Part I. Description of system. Brit J Radiol 1973;46:1016–1022. 2. Godfrey N. Hounsfield—Autobiography. Nobel e-Museum. Available at: http://www.nobel.se/medicine/laureates/1979/hounsfieldautobio.html. 3. Boyd DP, Lipton MJ. Cardiac computed tomography. Proc IEEE 1983;71:298–307. 4. Kalendar WA, Seissler W, Klotz E, Vock P. Spiral volumetric CT with single breath-hold technique: continuous transport and continuous scanner rotation. Radiology 1990;176:181–183. 5. Cody DD, Moxley DM, Davros W, Silverman PM. Principles of multislice computed tomographic technology. In: Silverman PM (ed), Multislice Computed Tomography. Lippincott, Williams, & Wilkins, Philadelphia: 2002;1–29. 6. Hunold P, Vogt FM, Schmermund A, et al. Radiation exposure during cardiac CT: effective doses at multi-detector row CT and electron-beam CT. Radiology 2003;226:145–152. 7. Stanford W, Rooholamini SA, Galvin JR. Ultrafast computed tomography for detection of intracardiac thrombi and tumors. In: Elliott LP (ed), Cardiac Imaging Imaging in Infants, Children, and Adults. JB Lippincott, Philadelphia: 2001;494–500. 8. Stanford W. Computed tomography and ultrafast computed tomography in pericardial disease. In: Elliott LP (ed), Cardiac Imaging in Infants, Children, and Adults. JB Lippincott, Philadelphia: 1991;415–420.

9. Stanford W. Electron-beam computed tomography in the evaluation of ischemic heart disease. In: Taveras JM, Ferrucci JT (eds), Radiology on CD ROM: Diagnosis-Imaging-Intervention. Lippincott, Williams and Wilkins, Philadelphia: 2002; Chapter 19:2. 10. Mochizuki T, Murase K, Higashino H, et al. Two- and three-dimensional CT ventriculography: a new application of helical CT. AJR Am J Roentgen 2000;174:203–208. 11. Wang T, Ritman EL. Regional myocardial perfusion-quantitation with high-speed, volume scanning CT (Abstract). Circulation 1987;76 (Part 2, Suppl.):IV–5. 12. Stanford W. Coronary artery calcification as an indicator of preclinical coronary artery disease. Radiographics 1999;19:1409–1419. 13. Becker CR, Jakobs TF, Aydemir S, et al. Helical and single-slice conventional CT versus electron beam CT for the quantification of coronary artery calcification. AJR Am J Roentgen 2000;174: 543–547. 14. Nallamothu BK, Saint S, Bielak LF, et al. Electron-beam computed tomography in the diagnosis of coronary artery disease: a metaanalysis. Arch Intern Med 2001;161:833–838. 15. Moshage WE, Achenbach S, Seese B, Bachmann K, Kirchgeorg M. Coronary artery stenoses: three-dimensional imaging with electrocardiographically triggered, contrast agent-enhanced, electron-beam CT. Radiology 1995;196:707–714. 16. Achenbach S, Moshage W, Ropers D, Nossen J, Daniel WG. Value of electron-beam computed tomography for the noninvasive detection of high-grade coronary-artery stenoses and occlusions. N Engl J Med 1998;339:1964–1971. 17. Achenbach S, Giesler T, Ropers D, et al. Detection of coronary artery stenoses by contrast-enhanced, retrospectively electrocardiographically-gated, multislice spiral computed tomography. Circulation 2001;103:2535–2538. 18. Schroeder S, Kopp AF, Baumbach A, et al. Noninvasive detection and evaluation of atherosclerotic coronary plaques with multislice computed tomography. J Am Coll Cardiol 2001;37-1430–1435 19. Mahesh M. Search for isotropic resolution in CT from conventional through multiple-row detector. Radiographics 2002;22: 949–962.

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TECHNICAL BACKGROUND II

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Electron Beam CT of the Heart DAVID G. HILL, PhD

INTRODUCTION

a group of magnets used to control and shape the beam. Two dipoles deflect the beam onto one of four fixed targets and sweep it along that target. A solenoid and two quadrupoles focus the beam and ensure a proper elliptical shape aligned so that the minor diameter of the ellipse is in the scan direction. The tungsten targets form a 210° arc and are backed by a watercooling system, allowing at least 20 s of continuous scanning at full power without reaching thermal limits. X-rays are generated as the electrons strike the tungsten and are collimated into a thin fan that irradiates the patient. The entire beam system, from electron source to target ring, is under vacuum and can be considered a very large, water-cooled, stationary X-ray tube. Reconstruction of a cross-sectional image from CT data requires that at least one ray in every direction pass through each pixel; a ray connects a source point and a detector (180° plus the X-ray fan angle). Current EBT geometry meets this requirement with a 216° detector and a 210° target, providing a 47.5-cm central region for imaging. X-rays from any of the four targets can reach the dual slice detector. If the targets are used in series, 76 mm of a patient can be seen without moving the patient. Brass collimation rings minimize the number of X-rays that could pass through the patient but not strike a detector. Collimation and detector size give dual 7-mm slices with any of the targets. For narrower slices, one target is used, and an additional collimator is employed to limit the X-ray beam to dual 1.5-, single 3-, or dual 3-mm slices as measured at the isocenter. This additional collimation is also prepatient, to give maximum dose utilization. During image reconstruction, the data for dual 1.5-mm slices can be combined to make a single 3-mm slice, and the data for dual 3-mm slices can be combined to make a single 6-mm slice. As in any CT scanner, X-rays are detected and digitized by solid-state detectors. Special EBT challenges are the high data rates and short integration times necessary to acquire sufficient data for an image in 33 ms or less. Reconstruction of these images requires that the data be corrected for beam hardening, beam and detector position, scattered X-rays, and incoming flux. The result is a cross-sectional CT image with very high temporal resolution and high spatial resolution. A single sweep is the passage of the electron beam along a target from beginning to end (210°), producing sufficient data to reconstruct an image. Most sweeps used for imaging move at constant angular velocity. A reset lasting 4–6 ms, during which no X-rays are generated, brings the beam back to the

Electron beam tomography (EBT)* was developed by Douglas Boyd, PhD, and his associates at Imatron, starting in 1977; the first clinical installation was at University of California at San Francisco in 1984. The challenge was to design a CT scanner capable of imaging the heart without motion artifacts; this required data acquisition times of 100 ms or less. In order to study perfusion, covering most of the heart without moving the patient table was also necessary. Acquisition times of 100 ms or less required a design with no moving parts except for the patient table. The result is EBT, where an electron beam generates the X-ray views needed for CT by sweeping across fixed targets. Since 1983, through several models, EBT has been continuously improved in spatial resolution, temporal resolution, and software capability, and has been distributed worldwide. In addition to the original anatomy, wall motion, and perfusion applications, applications such as measurement of coronary calcium, CT coronary angiography, lung studies, and standard CT radiological examinations have been developed and introduced. Unless otherwise stated, this article quotes specifications for the e-Speed™ model.

TECHNOLOGY EBT eliminates moving parts in the X-ray generation system by employing an electron beam that sweeps around a fixed tungsten-coated target to generate a fan of X-rays. The detector is mounted in a fixed position above the target ring, providing a fourth generation (fixed detector, moving beam) CT design. Sufficient data to reconstruct an image can then be acquired in one sweep of the beam around the target, which in the current model of the scanner (e-Speed) can be as short as 33 ms. The speed and position of the beam and data acquisition system are under computer control, allowing flexibility in the choice of temporal resolution, spatial resolution, and X-ray signal. The schematic shown in Fig. 1 is representative of an EBT system. The electron source accelerates electrons at potentials of up to 140 kV, producing a 1000-mA beam. Under high vacuum, the beam expands down a beam pipe until it reaches *Also referred to as EBCT in the published literature. From: Contemporary Cardiology: CT of the Heart: Principles and Applications Edited by: U. Joseph Schoepf © Humana Press, Inc., Totowa, NJ

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Fig. 1. Electron beam CT schematic.

Fig. 2. Typical W wire signal.

starting position for the next sweep. If the next sweep does not immediately follow the preceding sweep, the beam is either turned off or deflected to a beam stop downstream of the deflection coils, where it continues to move until the next sweep is commanded. Because of its high power, the electron beam can never be allowed to stop on the target without damaging the target. Protections against such damage are built into the hardware and software controlling the scanner. The geometry of the electron source requires the perveance, defined as V1.5/I, to be a constant; there is only one mA value for a given kV setting. Thus, an e-Speed with nominally 1000 mA at 140 kV has 895 mA at 130 kV. EBT calibration and data correction involve scanning of air to get incoming flux, measurement of water to set the CT number of water to 0, and correction of beam hardening and scattering to ensure uniformity of CT numbers in imaging of an organ or object with constant density. An additional EBT calibration is tuning, which is used to determine with high precision both the exact location of the beam with time, and the size, shape, and orientation of the beam spot. The beam condition at any given time is controlled by a sequence of coil currents vs time given to the magnets that steer and shape the beam. An EBT scanner has a fifth target, located beyond those used for patient studies; a series of three-wire bundles in a W shape are located in front of this target. As the beam sweeps over this target and crosses one of the W wires, the location of the peak on the central wire gives the time of the beam with respect to data acquisition; the width of the peak on the central wire gives the beam spot width; the shape and similarity of the pulses from the angled side wires give the orientation of the elliptical beam spot and its length; the distance between the side peaks is related to the beam radius from isocenter. An example of a W wire signal is shown in Fig. 2. The first part of tuning consists of adjusting the coil currents in time to give the desired parameters. Using equations that characterize the coil currents as a function of deflection angle, the tuned values are transferred to the sweep descriptions that will be used for scanning on the X-ray targets. The second part of tuning is a scan, with the transformed coil current values, of

a phantom containing a set of pins. Analysis of the raw data from the pin scans gives the reconstruction system the location of the beam corresponding to the data as acquired, enabling interpolation of the raw data to the positions required by the reconstruction algorithm. Control of the scanner requires numerous computers networked together, dealing with control of the beam, collimation, table, power supply, data acquisition, reconstruction, and operator interaction.

SCAN MODES Standard sweep speeds with the e-Speed are 33 ms, 50 ms, and 100 ms. Scan modes consist of different combinations of a series of sweeps on one or more targets, with patient-table motion or with no patient-table motion, and/or with an electrocardiogram (ECG) or timed trigger. If the patient table is not programmed to move while a sweep is being executed, the result is an axial scan mode. Axial scans, triggered from an ECG signal, are typical for cardiac studies. If the patient table moves while the X-rays are on, the result is a continuous volume scan, analogous to a spiral or helical scan with a mechanical CT. Continuous volume modes are typically used for CT angiographic studies of the great vessels, for example. An external ECG monitor generates triggers at the R wave. Sweeps begin at a user-specified time after the R wave, which can be set either as a time interval in seconds or as a percentage of the RR interval. If triggering is based on percentages, the time is estimated from the previous seven heart RR intervals and thus adapts to changes in the heart rate. Extensive clinical studies (1) show, for an EBT scanner with its high temporal resolution, that the point in the RR interval with minimum motion is about 300 ms after the R wave, near the end of the T wave. Since the length of systole (starting at the R wave) tends to be more constant with heart-rate change than the length of diastole, triggering at the end of the T wave (end systole) seems to have fewer problems with irregular heart rates than does triggering by percentage of the RR interval. EBT scanners use prospective triggering. Before the scan begins, a point (or points) in the heart cycle is chosen for the sweep to occur, and only those data are acquired and recon-

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Fig. 3. (A) ECG trace—single trigger at end systole (represented by
). (B) ECG trace—triggering eight phases of the heart. (C) ECG trace— triggering at two positions within the heart cycle.

structed. Therefore, all exposure of the patient contributes to the study images; high temporal resolution and accurate triggering algorithms make this both feasible and efficient. The simplest ECG-triggered scan mode has one sweep after the trigger at a prespecified time after the R wave; patient-table motion is after the sweep, so the patient table is at rest in the new position in time for the next scan. This is the scan mode used for a coronary calcium study or for an electron beam angiography (EBA) study (contrast in the arteries) with dual 1.5-mm, single 3-mm, or dual 3-mm collimation. Table increment is usually equal to the collimation, although smaller increments giving overlapping images are used in some cases. Instead of just one sweep after the trigger, more than one sweep can be used, with each sweep immediately following its predecessor. The patient table moves to its next position after the set number of sweeps has been performed. This allows

studies of the heart at multiple phases in the same study time as a single-phase study, and allows the clinician to appreciate changes in the heart over the heart cycle. Multiple phases is a cine mode including patient-table motion, and is used with all collimations. The high temporal resolution gives minimal motion artifact at any phase. A further generalization of this mode allows the user to position sweeps at any point throughout the heart cycle. For example, this might be used to scan at approximately end systole and end diastole to obtain a measurement of ejection fraction. Figure 3 shows a representative ECG trace with several possible triggering modes indicated. For any ECG-triggered mode with patient-table motion, if the time required for the number of sweeps requested plus the patient-table motion is less than the RR interval, the table is positioned for the next location when the time to start the next

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Table 1 Selected Specifications Specification

C150

Sweep speeds-thin slices Sweep speeds-multitarget Thin slice collimation Multitarget collimation In-plane spatial resolution

100 ms 50 ms 1.5, 3, and 6 mm dual 7 mm 7 line pairs (lp)/cm (100 ms)

100 ms 50 ms 1.5, 3, and 6 mm dual 7 mm 9.5 lp/cm (100 ms)

Power

83 kW (130 kV, 625 mA)

83 kW (130 kV, 625 mA)

Trigger times (%RR)

40–80 (all) 0 (50 ms only) 0.273–0.999

40–80 (all) 0 (50 ms only) 0.273–0.999

Trigger times (seconds after R)

e-Speed

C300 / C150 High Resolution

set of sweeps arrives; if the patient table is not in place for the next heart cycle, one heart cycle is skipped. A multitarget cine study, typically covering the entire heart cycle, can also be performed. Sweeps every 33, 50, or 100 ms from the first target cover the time between first and second R waves; the second target is used to cover the third to fourth R-wave interval, the third target with the fifth to sixth R-wave interval, and the last target with the seventh to eighth R-wave interval. If more coverage is needed, the patient table is then moved 40 mm or more and additional scans taken. A flow study is used to follow a bolus of contrast. One or more sweeps is taken each heart cycle without patient-table motion. If all four targets are used, then one sweep is taken on each of the targets during one heart cycle, allowing the measurement of perfusion over 76 mm of the body using the same contrast bolus. Some heart cycles are usually skipped to sample the bolus curve but minimize dose. This is the standard mode for the measurement of myocardial perfusion. All of these modes can be triggered manually or by time instead of by ECG; however, cardiac studies are almost always ECG-triggered. If the table moves while the beam sweeps continually, the result is a continuous volume scan, similar to a helical or spiral scan with a mechanical CT. Data can be acquired with any of the available collimations. Images are reconstructed at any location along the scan; the slice width in the image is determined from the collimation and the table travel corresponding to the sweeps included in the reconstruction. As an EBT scanner has a fixed mA for a given kV, in order to change the exposure in an image without changing the slice width, the speed of the patient table must also change. For example, in a study using 3-mm collimation and reconstructing a 3-mm slice, twice the exposure in the 3-mm slice requires the patient table to move half as fast. A continuous volume scan is the normal scan mode for studying the noncardiac vessels, the lungs, abdomen, or any other organ not requiring ECG triggering. Of course, the axial modes described previously with a timed or manual trigger may also be used; however, the study time is longer than with continuous

33, 50, and 100 ms 33, 50, and 100 ms dual 1.5 mm, single 3 mm, dual 3 mm dual 7 mm 10 lp/cm (50 ms) 13 + lp/cm (100 ms) 7 lp/cm (33 ms) 140 kW (140 kV, 1000 mA) 116 kW (130 kV, 895 mA) 0–99 (all) 0.060–1.500

volume scanning but without patient-table motion during data acquisition. A PreView™ (General Electric, formerly Imatron) (scout or localization scan) is created using a special sweep while the patient table moves continuously. The beam is swept very rapidly along the tuning target; near three o’clock and again near six o’clock, the beam moves onto the X-ray target for a short arc at the slower 50-ms speed. X-rays reaching the patient are generated only when the beam is on the X-ray target. A transmission image is synthesized from the source points along these arcs, giving views in both anterior/posterior and lateral directions. From these views the user not only can set the location in the patient direction to start and stop acquiring data, but also can set the center point and field of view for the reconstructed images in the studies to follow. Because PreView images are made from a number of source positions through a process of tomosynthesis, the plane of focus can be changed from the default value of the isocenter, or multiple planes can be computed and viewed. The depth of field is sufficiently large that isocenter is normally chosen.

IMAGE QUALITY EBT is designed for high temporal resolution: 33, 50, or 100 ms in a single image without requiring data from more than one heart cycle. This temporal resolution is short enough that images can be acquired at any point in the heart cycle with no or almost no motion artifact. Maximum in-plane resolution ranges from 7 line pairs (lp)/ cm at 33 ms to 13 lp/cm at 100 ms. An extensive set of reconstruction kernels allow the optimization of resolution to the clinical study being performed. Narrowest slices are 1.5 mm. Because the arteries are typically moving from 20 to 100 mm/ sec (2), resolving the arteries clearly requires a high temporal resolution imaging system.

SPECIFICATIONS As of this writing there are three EBT models in clinical use: C150, C300, and e-Speed. Some critical parameters such as sweep speed, slice width, and resolution are summarized in Table 1.

CHAPTER 2 / ELECTRON BEAM TOMOGRAPHY

DOSE As an EBT scanner irradiates a patient over a 210° arc (essentially from two o’clock to ten o’clock), dose near the surface of the patient is not uniform. For a patient lying supine, dose is a factor of five lower anterior than it is posterior. The result is that dose to the breast is minimized during a cardiac examination. Prospective triggering also means that a patient receives only the dose necessary for the images desired for the study. The user can choose to acquire data over the entire heart cycle or over only a part of it, and the scanner acquires just those data. Table 2 gives the CT dose index (CTDI) (3) information for a scan that would be typical of a calcium or coronary angiographic single-phase study for an EBT scanner, as well as an estimate of the effective dose (E) if the entire heart is covered. The 32-cm body CTDI is quoted with a 3-mm slice (or dual 1.5-mm with e-Speed) and a single sweep. The CTDI as defined is an estimate of the single-slice dose taking into account the tails of the dose profiles from the adjacent slices. E is estimated (4) by multiplying the CTDIvol (weighted CTDI adjusted for table speed) times the distance covered (which is the dose-length product) × 0.017.

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Table 2 Dose Information Parameter CT dose index (CTDI) at A (center) CTDI at B (12 o’clock) CTDI at C (6 o’clock) CTDI at D,E (3 or 9 o-clock) CTDIw (weighted average)

C150/C300 1.8 mGy 1.2 mGy 7.9 mGy 5.6 mGy 3.7 mGy

e-Speed 1.9 mGy 1.2 mGy 6.3 mGy 5.1 mGy 3.6 mGy

Typical cardiac studies covering entire heart with one sweep each heart cycle: kV mA Sweep time Collimation Table increment/heart cycle Effective dose

130 625 100 ms 3 mm 3 mm 0.7 mSv

140 1000 50 ms 3 mm 3 mm 0.7 mSv

Sweep time Collimation Table increment/heart cycle Effective dose

100 ms 1.5 mm 1.5 mm 1.4 mSv

50 ms dual 1.5 mm 3 mm 0.7 mSv

TYPICAL APPLICATIONS Typical cardiac studies with EBT include coronary calcium (5), EBA of the coronary arteries (6,7), cardiac anatomy (8), wall motion studies (9), and perfusion studies (10). EBT scanners are also excellent vehicles for CT angiography of the noncardiac vessels, as well as for lung studies (11) . The references given are to published studies as examples; no attempt has been made to make this a complete bibliography. Figure 4 is an example of an axial image showing coronary calcium; Fig. 5 shows a 3D volume rendering of an EBA study, and Fig. 6 shows a maximum intensity projection image of the same data set. Studies of coronary calcium use an ECG-triggered axial mode with one phase/heart cycle. Most recently the preferred trigger point is near end systole, a time of minimum motion of the right coronary (1) with a 3-mm slice, 130 kV, and no contrast. Historically, most coronary calcium scanning has been done with triggering either near 80% or more recently near 40% of the RR interval. All EBT scanner models have a calcium scanning mode that matches slice width, reconstruction parameters, and kV to the early data on C100/C150, so that the Agatston (12) score for calcium is independent of EBT model; thus, historical data can be used for clinical comparison. Other scoring methods such as volume score (13) and mass score (14) have been proposed and implemented that may be more independent of the scan mode. Coronary angiographic studies (electron beam angiography, or EBA) use ECG-triggered axial modes with one or more phase/heart cycle and intravenous contrast injection. If a single phase is used, then the scanner is triggered at the point of minimum motion; if multiple phases are being used, then the point of minimum motion is usually included as one of the phases. In order to optimize the contrast, circulation time is determined before an EBA study, using a short bolus of contrast and a flow study looking at a given level. Typically a scan is triggered at the start of contrast injection (for a baseline value

without contrast); some 6–10 heart cycles later a sequence of one sweep every other heart cycle begins through the expected peak of the contrast (18 s or so) followed by a sweep every 3 heart cycles or so to follow the contrast wash out. The circulation time (the time between injection and arrival at the coronary arteries) is then determined from the change in the CT number in the aorta or left ventricle with time. EBA data acquisition starts after a delay from the start of injection that is approximately equal to the circulation time. If the circulation time study uses all four targets and the dual 7-mm collimation, it becomes a perfusion study. The length of the EBA injection should be approximately equal to the time required to complete the series, estimated from the distance to cover (which when divided by the table increment gives the number of heart cycles needed) and the starting heart rate. For most patients, the heart rate will increase during the study. Optimization of the contrast is very important; in addition to correct circulation time and injection duration, it may involve a saline chaser and variation of the contrast flow rate during the injection. The best studies come with the contrast signal uniform in time and the ratio of the average CT number of the contrasted vessels to the X-ray noise in the images as large as possible. Most EBA studies are analyzed on a workstation making use of reformats, maximum intensity projections, and volume renderings to appreciate the details of the arteries. Multiple-phase EBAs make arterial motion obvious, although any individual phase can be analyzed. Clinical evaluation of the data frequently includes observing 2D and 3D renderings “beat” as the display cycles through the phases. With an appropriate choice of scan parameters, the study may cover a sufficient portion of the heart cycle to allow the estimation of ejection fraction. Valve motion can also be visualized.

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HILL

Fig. 4. Calcium example; 3-mm slice; 130 kV; 895 mA; 50 ms.

Fig. 5. Three-dimensional rendering of an electron beam angiography study; dual 1.5-mm slice; 140 kV; 1000 mA; 50 ms.

Fig. 6. Maximum intensity projection image of left anterior descending artery; same data set as Fig. 5.

CHAPTER 2 / ELECTRON BEAM TOMOGRAPHY

Sufficient cardiac functional information is often gathered from a multiphase study. In addition, there are two ways to perform a dedicated wall-motion or function study. One is essentially an EBA using dual 7-mm collimation covering the entire heart cycle, with a 15-mm patient-table motion every other heart cycle. An alternative, avoiding patient-table motion, is to move the beam sequentially through the different targets instead of moving the patient table. A perfusion study is a circulation time study with 76-mm coverage, using all four targets and the dual 7-mm collimation. This mode allows the measurement of perfusion throughout the myocardium using one bolus of contrast. There are three gaps of approx 5 mm each (between the targets) that are not fully illuminated. A complete EBCT cardiac exam consists of a PreView for localization, a calcium study, a flow study used for both perfusion and circulation time determination, a multiphase EBA, and possibly a wall-motion study using residual contrast from the EBA. The EBCT patient table can tilt 25° and slew ± 25° (side to side in the horizontal plane). Tilt and slew allow the acquisition of wall-motion or perfusion data in approximately the short axis position (tilt 15°, slew –15° to –25°) or the long axis position (tilt 0°, slew +25°), approximating traditional cardiac views. Continuous volume is the mode of choice to analyze the noncardiac vessels, yielding clear motion-free images. For example, using on the e-Speed dual 1.5-mm collimation , 50-ms sweeps, and a 3-mm table increment, the patient table moves at 54 mm/s, allowing most areas of interest to be covered in 10 s or less.

FUTURE DIRECTIONS EBCT scanners are designed for excellent cardiac imaging. There is no inherent limit on how fast an EBCT scanner can sweep the beam, as there are no moving parts, so sweep times can become even shorter, improving temporal resolution. Potential temporal resolution is limited only by available X-ray power (signal-to-noise in the images) and data acquisition speeds. Future directions are likely to include using a detector with smaller elements for thinner slices, as well as increasing

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the number of detectors in the patient direction for increased coverage with each sweep. As cardiac imaging continues to grow in clinical importance, EBT is an ideal modality for improved applications and efficient usage.

REFERENCES 1. Mao S, Budoff MJ, Bakhsheshi H, Liu SC. Improved reproducibility of coronary artery calcium scoring by electron beam tomography with a new electrocardiographic trigger method. Invest Radiol 2001;36(7):363–367. 2. Achenbach S, Ropers D, Holle J, Muschiol G, Daniel WG, Moshage W. In-plane coronary arterial motion velocity: measurement with electron-beam CT. Radiology 2000;216(2):457–463. 3. Title 21 Code of Federal Regulations Part 1020 Section 33(c)(2)(i). 4. McCullough C. Patient dose in computed tomography of the heart. Herz 2003;28:1–6. 5. Budoff MJ, Raggi P. Coronary artery disease progression assessed by electron-beam computed tomography (review). Am J Cardiol 2001;88(2A):46E–50E. 6. Achenbach S, Moshage W, Ropers D, Nossen J, Daniel W. Value of electron beam computed tomography for the noninvasive detection of high-grade coronary-artery stenoses and occlusions. N Engl J Med 1998;22:1964–1971. 7. Lu B, Zhuang N, Mao S, Bakhsheshhi H, Liu S, Budoff M. Image quality of three-dimentional electron beam coronary angiography. J Comput Assist Tomogr 2002;26:202–209. 8. Westra S, Hurteau J, Galindo A, McNitt-Gray M, Boechat M, Laks H. Cardiac electron-beam CT in children undergoing surgical repair for pulmonary atresia. Radiology 1999;213:502–512. 9. Rumberger JA. Use of electron beam tomography to quantify cardiac diastolic function (review). Cardiol Clin 2000;18(3):547–556. 10. Bell MR, Lerman LO, Rumberger JA. Validation of minimally invasive measurement of myocardial perfusion using electron beam computed tomography and application in human volunteers. Heart 1999;81:628–635. 11. Robinson T, Leung A, Moss R, Blankenberg F, Al-Dabbagh H, Northway W. Standardized high-resolution CT of the lung using spirometer-triggered electron beam CT scanner. AJR Am J Roentgenol 1999;172:1636–1638. 12. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15:827–832. 13. Callister TQ, Cooil B, Raya SP, Lippolis NJ, Russo DJ, Raggi P. Coronary artery disease: improved reproducibility of calcium scoring with an electron-beam CT volumetric method. Radiology 1998;208:807–814. 14. Utzheimer S, Kalender W. Assessment of calcium scoring performance in cardiac computed tomography. Eur Radiol 2003;13:484–497.

CHAPTER 3 / MULTISLICE SCAN TECHNIQUES

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Scan Techniques for Cardiac and Coronary Artery Imaging With Multislice CT BERND M. OHNESORGE, PhD, BRIAN R. WESTERMAN, PhD, AND U. JOSEPH SCHOEPF, MD

INTRODUCTION

provided much more accurate CT imaging of the heart and the coronary arteries (11–14). Recent clinical studies have demonstrated the potential of MSCT to differentiate and classify lipid, fibrous, and calcified coronary plaques (15). Despite these promising advances, the 4-slice CT scanner technology still faces some challenges and limitations with respect to motion artifacts in patients with higher heart rates, limited spatial resolution, and long breath-hold times (12). In 2001, a new generation of MSCT systems with simultaneous acquisition of up to 16 slices was introduced (16,17). With submillimeter slice acquisition and gantry rotation times shorter than 0.5 s, both spatial and temporal resolution are improved, while examination times are considerably reduced. In this chapter, we present the basic technology of MSCT cardiac scanning with a special focus on recommended scan techniques for different clinical applications. We will also discuss the technology advances and improved clinical performance of state-of-the-art 16-slice CT equipment compared with 4-slice CT scanners.

Cardiac imaging is a demanding application for any noninvasive imaging modality. On the one hand, high temporal resolution is needed to virtually freeze cardiac motion and thus avoid motion artifacts in the images. On the other hand, sufficient spatial resolution—at best submillimeter—is required to adequately visualize small and complex anatomical structures like the coronary arteries. The complete heart volume has to be examined within a single short breath-hold time to avoid breathing artifacts and to limit the amount of contrast agent, if necessary. The motion of the heart is both complex and very fast. Some estimates of the temporal resolution needed to freeze cardiac motion in any phase of the cardiac cycle are as low as 10 ms. In 1984, electron beam computed tomography (EBCT) was introduced as a noninvasive imaging modality for the diagnosis of coronary artery disease (1–4). Its temporal resolution of 100 ms allows for relatively motion-free imaging of the cardiac anatomy in the diastolic phase, even at higher heart rates. Because the EBCT at that time was limited to axial scanning for electrocardiogram (ECG)-synchronized cardiac investigations, a single breath-hold scan of the heart required slice widths of at least 3 mm. The resulting axial resolution was therefore limited and not adequate for 3D visualization of the coronary arteries. With the advent of subsecond rotation, combined with prospective and retrospective ECG-gating, mechanical single-slice helical or spiral CT systems with superior general image quality entered the realm of cardiac imaging (4,5). Since 1999, 4-slice CT systems, which have the potential to overcome some of the limitations of single-slice cardiac CT scanning, have been used to establish ECG-triggered or ECGgated multislice CT (MSCT) examinations of the heart and the coronary arteries in clinical use (6–10). As a result of the increased scan speed with four simultaneously acquired slices, coverage of the entire heart volume with thin slices within one breath-hold became feasible. The improved axial resolution

TECHNOLOGY PRINCIPLES TECHNOLOGY OVERVIEW

CT examinations of the heart should be performed in a single, short breath-hold scan with high temporal resolution to eliminate cardiac motion and high, preferably isotropic, spatial resolution. It has become increasingly apparent that submillimeter slices are necessary to adequately visualize small and complex cardio-thoracic anatomy and the coronary arteries. In 1984, EBCT was introduced as the first cross-sectional noninvasive imaging modality that could visualize the cardiac anatomy and the coronary arteries (1). During this period, mechanical scanners typically had single-slice detectors and a minimum gantry rotation time of 0.75–1.0 s, and were not considered of value for strictly cardiac imaging. With presently available EBCT scanners, temporal resolution of 100 ms provides motion-free images of the cardiac anatomy in the diastolic phase of the cardiac cycle even at higher heart rates (2). Cardiac anatomy can be covered in a single breath-hold of 30– 40 s with slice widths of 3 mm, but this limits the diagnostic

From: Contemporary Cardiology: CT of the Heart: Principles and Applications Edited by: U. Joseph Schoepf © Humana Press, Inc., Totowa, NJ

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accuracy of coronary artery visualization (3). In 1998, spiral/ helical CT systems with simultaneous acquisition of four detector slices and rotation time of 500 ms were introduced (6,7,10), which provided a substantial performance increase over the single- and dual-slice spiral CT systems that had been available until then. These MSCT scanners can cover larger scan volumes with slice collimation down to 0.5 mm and thus provide higher spatial resolution for improved visualization of small and complex anatomy. Detector configurations in use today enable simultaneous collimation of four slices with different slice widths. In the “fixed array” design, detector rows with equal spacing are used, while the “adaptive array” and “hybrid” detector designs consist of fewer detector rows, containing elements that become wider away from the center of the detector (Fig. 1A,B). In all designs the thinnest slices result from collimation of the inner four detector rows, and thicker slices are generated by electronic combination of adjacent detector rows. Regardless of detector design, it was apparent from the operation of the 4-slice scanners that no fundamental barrier prevented the construction of CT scanners that could acquire more slices simultaneously, and indeed this quickly came to pass. Systems capable of eight slices became available in 2000, with commensurate increases in exam speed. Meanwhile, 8- and 10-slice CT scanners are being used that provide further improved volume coverage with about 1-mm slice width and 500 ms rotation time (18). The first 16-slice CT scanners, introduced in early 2002, provide faster rotation time (down to 400 ms) and submillimeter detector collimation for routine volume imaging (16,17). The 16-slice systems are sufficiently fast to cover the entire heart, scanning with submillimeter slices, in a reasonable breath-hold. All of the 16-slice scanners have adopted a detector design with elements of two sizes. In the examples given (SOMATOM Sensation 16, Siemens, and Aquillion 16, Toshiba Medical) (Fig. 1C,D) the 16 central rows define submillimeter detector acquisition. By adding outer detector rows on both sides, wider slices of 1 mm and above can be achieved. Higher temporal resolution than the older mechanical CT scanners is provided by a combination of faster gantry rotation speed, with rotation times down to 500 ms, and specialized reconstruction algorithms (10). As of 2002, the shortest gantry rotation time was reduced to 400 ms, and more recently even to 370 ms, thus further improving temporal resolution (16,17). The combination of fast rotation time and multislice acquisition with submillimeter spatial resolution has proved to be of particular importance for improved cardiac image quality (17,19–21). Motion artifacts caused by cardiac pulsation can be minimized in high-resolution CT studies by limiting image reconstruction to those parts of the cardiac cycle associated with the least motion, typically during diastole. The heart phases can be determined from a simultaneously recorded ECG signal. Two different ECG synchronization techniques are most commonly employed for cardiac CT scanning—prospective ECG triggering and retrospective ECG gating.

ECG-TRIGGERED MSCT IMAGING

Prospective ECG triggering has long been used in conjunction with EBCT and single-slice spiral CT (1–4). A trigger signal is derived from the patient’s ECG based on a prospective estimation of the present RR interval, and the scan is started at a user-defined time after a detected R wave, usually during diastole. MSCT allows simultaneous acquisition of several slices in one heartbeat with a cycle time that usually allows scanning in every other heartbeat (Fig. 2A). Thus shorter breathhold times are required compared to single-slice scanners, and respiratory artifacts can be virtually eliminated. To achieve the best possible temporal resolution, scan data are acquired only during a partial gantry rotation (approximately two thirds of a rotation with 240–260° projection data) that covers the minimum amount of data required for image reconstruction. Conventional partial image reconstruction based on fan beam projection data results in a temporal resolution equal to the acquisition time of the partial scan. Optimized temporal resolution can be achieved with parallel-beam-based “half-scan” reconstruction algorithms that provide a temporal resolution of half the rotation time in a central area of the scan field of view (6,7,10,16). Thus, prospective ECG triggering is also the most dose-efficient method of ECG-synchronized scanning, as only the very minimum of scan data needed for image reconstruction are acquired. However, usually only relatively thick slices (3 mm with EBCT, 2.5–3 mm with 4-, 8-, and 16-slice CT) are used for prospectively triggered acquisition, to maintain a reasonably short single breath-hold. Thus, resulting data sets are often not suitable for 3D or multiplanar reformation (MPR) reconstruction of small cardiac anatomy. In addition, prospective ECG-triggered scans are sensitive to changes in heart rate during acquisition, so significant fluctuation or arrhythmia can have a severe effect on image quality. ECG-GATED MSCT SCANNING AND IMAGE RECONSTRUCTION

Retrospective ECG gating overcomes the limitations of prospective ECG triggering with regard to scan time and spatial resolution, and can provide more consistent image quality for examination of patients with changing heart rate during the scan. This technique requires multislice spiral scanning with slow table speed and simultaneous recording of the ECG trace that is used for retrospective assignment of image reconstruction (8–10). Phase-consistent coverage of the heart requires a highly overlapping spiral/helical scan with a table feed adapted to the heart rate in order to avoid gaps between image stacks that are reconstructed in consecutive heart cycles. The image stacks are reconstructed at exactly the same phase of the heart cycle and cover the entire heart and adjacent anatomy (Fig. 2B). To achieve gapless coverage of the entire heart over a wide range of heart rates, pitch values between 0.2 and 0.4 are employed (pitch equals table feed per rotation, divided by the nominal width of the X-ray beam—equal to all slices combined). Images are reconstructed during every heart beat, and somewhat faster scan coverage is possible as compared to prospective ECG triggering. Moreover, the continuous spiral acquisition enables reconstruction of overlapping image slices,

CHAPTER 3 / MULTISLICE SCAN TECHNIQUES

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Fig. 1. (A) Equally spaced detector elements build the fixed array detector (FAD) for a 4-slice system. Different 4-slice collimation settings (4 × 1.25, 4 × 2.5, 4 × 3.75, 4 × 5 mm) are produced by electronic combination of adjacent elements. (B) Differently sized detector elements build the adaptive array detector (AAD) for a 4-slice system. Different 4-slice collimation settings (4 × 2.5, 4 × 5 mm) are produced by electronic combination of adjacent elements. For 4 × 1 mm collimation, partial shielding of the elements with 1.5-mm width is required. Partial illumination of the inner two detector elements allows for 2 × 0.5-mm collimation for high-resolution scanning. (C) The latest 16-slice CT scanners are also based on the AAD design with differently sized detector elements. 16-slice collimation settings 16 × 0.75 mm and 16 × 1.5 mm are produced by equally spaced 16 × 0.75-mm detector elements in the center, eight additional 1.5-mm detector elements (four on each side), and electronic combination of adjacent elements. (D) Other 16-slice CT designs allow for illumination of 16 × 0.5-mm slices in the detector center and up to 16 × 2.0-mm slices via adding detector elements with 1.0-mm detector spacing on each side that are also electronically combined.

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Fig. 2. (A) Illustration of sequential volume coverage with prospectively ECG-triggered multislice scanning. Multiple images (one image per detector slice) are acquired at a time with a certain delay after a detected R wave. The slice thickness is equivalent to the collimation (hatched blocks), and the temporal resolution equals half the rotation time. Owing to the limitation of the scan cycle time to about 1 s, a scan can be acquired every other heart cycle for usual heart rates. (B) A scan with continuous table feed and continuous exposure is acquired for retrospectively ECG-gated multislice spiral scanning. Stacks of overlapping images can be reconstructed with a temporal resolution of half the rotation time in every cardiac cycle. Continuous 3D images can be reconstructed in different phases of the cardiac cycle by selection of the data ranges with certain phase relations to the R waves.

and thus a longitudinal spatial resolution about 20% below the slice width can be achieved (e.g., 1.0 mm for 1.25-mm slices, 0.8 mm for 1.0-mm slices, 0.6 mm for 0.75-mm slices, 0.5 mm for 0.6-mm slices). For these reasons, retrospective ECG-gated reconstruction is the preferred method for imaging cardiac anatomy and the coronary arteries. Thin slices provide the necessary spatial resolution for diagnosis within a breath-hold time that can be managed by most patients. Reconstructing images from fan beam data of a partial rotation (usually 240–260°) within every cardiac cycle yields a temporal resolution equal to half of the gantry rotation time. A multislice spiral interpolation between the projections of adjacent detector rows is used in order to compensate for table movement and to provide a well-defined slice sensitivity profile and images free of spiral artifacts. The temporal resolution can be improved by using scan data from more than one heart cycle for reconstruction of an image (“segmented reconstruction”) (9,22,24) (Figs. 3 and 4). While the number of fan beam projections needed to reconstruct the image remains the same, collecting them from multiple (up to four) consecutive cardiac cycles reduces the data collection time in each cycle and thereby improves temporal resolution. Depending on the relationship between rotation time and patient heart rate, a temporal resolu-

Fig. 3. (A) Schematic illustration of an adaptive segmented image reconstruction approach for electrocardiogram (ECG)-gated 16-slice spiral CT scanning. Dashed lines are used to indicate the z positions of the detector slices, which continuously and linearly change position relative to the patient with constant spiral feed. The ECG signal is simultaneously recorded during scan acquisition and is displayed at the bottom of the diagram. At heart rates below a certain threshold, one segment of consecutive multislice spiral data is used for image reconstruction. At higher heart rates, two sub-segments from adjacent heart cycles contribute to the partial scan data segment. In each cardiac cycle, a stack of images is reconstructed at different z positions covering a small sub-volume of the heart, which is shown as a box. The combination of sub-volumes from all heart cycles during the scan provides a continuous 3D data set of the entire heart. (B) Temporal resolution as a function of the heart rate for the adaptive segmented reconstruction approach, using 0.5-s, 0.42–s, and 0.37-s gantry rotation time. If data from two consecutive heart cycles are used for image reconstruction, the temporal resolution strongly depends on heart rate. For 0.42-s rotation time, the temporal resolution reaches its optimum of 105 ms at 81 bpm; for 0.37 s the optimum of 92 ms is present at 71 bpm. Thus, clinically robust image quality can be achieved also in patients with higher heart rates, i.e., in patients with stable sinus rhythm and heart rates in the range 75–85 bpm.

tion between (rotation time)/2 and (rotation time)/2 × M is possible (where M equals the number of segments or heart cycles used). Most recent cardiac reconstruction algorithms automatically adapt the number of heart cycles used with changing heart rate during the scan, in order to optimize temporal resolution if higher heart rates are present (Figs. 3 and 4). While the use of segmented reconstruction may extend cardiac imag-

CHAPTER 3 / MULTISLICE SCAN TECHNIQUES

Fig. 4. (A) Schematic illustration of an alternative adaptive segmented image reconstruction technique for electrocardiogram-gated 16-slice spiral CT scanning with use of up to three segments per slice. (B) Temporal resolution as a function of the heart rate for this approach for 0.5-s and 0.4-s gantry rotation time. By using up to three segments per slice, temporal resolution can be further increased in patients with certain and very stable heart rate at the expense of slower table speed, thus resulting in higher radiation exposure and longer breath-hold times. When heart rate is 95–105 bpm, 0.5-s gantry rotation provides theoretically better temporal resolution than 0.4-s gantry rotation. Temporal resolution is a complex function of heart rate, gantry rotation time, and helical pitch.

ing with CT to higher heart rates, the associated drawback is slower table speed, resulting in increased patient dose and longer breath-holds. As with nonsegmented reconstruction algorithms, an irregular heart rate may severely compromise the study. Recent publications (16,23) have demonstrated that conebeam reconstruction algorithms become mandatory for general purpose CT scanning with eight and more slices to avoid severe image artifacts. The severity of cone-beam-induced artifacts depends on the number of simultaneously acquired slices, on the width of each slice, and on the distance between an object

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and the center of rotation. Cone-beam artifacts are most pronounced at high-contrast boundaries. Typical sources of conebeam artifacts are the ribs or the pelvic bones. Because the heart is usually well centered and does not contain large high-contrast structures, cone-beam artifacts are negligible for today’s 16-slice CT scanners (20,21). Since cone-beam reconstruction algorithms are computationally intensive, they tend to be time consuming. If they are not needed for ECG-gated cardiac scanning, then the time can be better utilized for more rapid reconstruction using less complex algorithms. Cardiac CT scanning with more than 16 slices, however, will require advanced cardiac cone-beam algorithms in future CT systems (25). Usually the diastolic phase of the cardiac cycle is chosen for image reconstruction of cardiac and coronary morphology; however, owing to the highly overlapping scan acquisition, image data can be reconstructed for each x, y, and z position within the scanned volume over the entire course of the cardiac cycle. This allows for retrospective selection of phases for reconstruction that provide the best image quality for anatomy with special motion patterns in individual patients (26,27). To improve image quality in the presence of arrhythmia, selected image stacks can either be discarded or arbitrarily shifted within the cardiac cycle, so that reconstruction always coincides with the same interval during diastole at each level of the cardiac volume. Besides the morphological information that is derived from images reconstructed in diastole, additional reconstructions of the same scan data set in different phases of the cardiac cycle (Fig. 2B) enable analysis of basic cardiac function parameters such as end-diastolic volume, end-systolic volume, ejection fraction, and regional wall motion. Relatively high radiation exposure is associated with retrospectively ECG-gated imaging of the heart because of continuous X-ray exposure and overlapping data acquisition at low table speeds. All data can be used for image reconstruction in different cardiac phases, but if only a very limited interval (i.e., diastolic phase) in the cardiac cycle is targeted during reconstruction, a significant portion of the acquired data and radiation exposure is redundant. A high potential for exposure reduction during ECG-gated spiral scanning is offered by an on-line reduction of the tube output within each cardiac cycle during phases that are of less importance for ECG-gated reconstruction (10). In this approach, the nominal tube output is applied only during the diastolic phases of the cardiac cycle that are likely to be reconstructed. In the rest of the cardiac cycle, the tube output is reduced. Depending on the heart rate, an overall exposure saving of 30–50% can be achieved without compromising on image quality (28). This technique is particularly useful for examination of coronary artery calcification. For coronary CT angiography in patients with higher heart rates, optimal images of the different coronary vessels may need to be reconstructed in wider ranges of the RR interval, leaving little time in which to reduce tube current. A special technique for ECG-gated spiral scanning with increased volume coverage for cardio-thoracic applications has been introduced for 4-slice CT scanners (29). It allows for suppression of cardiac pulsation by means of reconstruction with a temporal resolution that equals half the rotation time, and to

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Fig. 5. Investigation of the spatial resolution in the scan direction for cardiac CT examinations with 4- and 16-slice CT with a resting longitudinal resolution phantom. The phantom includes air-filled spheres 0.4 to 3.0 mm in diameter that can be examined with multiplanar reformation cuts along the scan direction. A maximum longitudinal resolution of 0.8–1.0 mm can be achieved with 4-slice CT using 4 × 1-mm collimation, 1.3-mm slice width, 0.6-mm image increment, and 3-mm/s table feed. 16-slice CT provides up to 0.6-mm longitudinal resolution based on 16 × 0.75-mm collimation, 0.8-mm slice width, 0.4-mm image increment, and 6.6-mm/s table feed.

ECG gating that eliminates scan data acquired during the systolic phase, with its rapid heart motion. The latest 16-slice CT scanners equipped with this protocol can provide motion-free coverage of the entire thoracic anatomy with submillimeter slices within a single breath-hold. However, cone-beam reconstruction techniques may be required for this application, as high-contrast thoracic anatomy located in the periphery of the scan field of view is also of interest for diagnosis (30). PERFORMANCE EVALUATION WITH PHANTOM STUDIES

The performance of 4-slice CT scanners in comparison to a new 16-slice CT scanner with respect to cardiac imaging has been evaluated with computer simulation studies and phantom measurements. The results demonstrate the advancements of 16-slice CT scanners in scan speed and spatial resolution. The achievable spatial resolution with high-resolution cardiac scan protocols is demonstrated with a z resolution phantom (Fig. 5). The z resolution phantom consists of a Lucite plate with rows of cylindrical holes of different diameters in the transverse direction. The 4-slice CT scanner with 4 × 1 mm collimation, 0.5 s rotation speed and 3 mm/s table feed (pitch 0.375) can resolve structures of 1.0 mm in size using 1.3 mm reconstructed slice width and 0.5 mm image increment. With 16-slice CT technology and submillimeter collimation the spatial resolution is improved even at higher scan speed. Based on 16 × 0.75 mm collimation, 0.42 s rotation speed and 6.6 mm/s table feed (pitch 0.31), 0.6 mm sized objects can be delineated using 0.8 mm reconstructed images and 0.4 mm image increment. A computer model of an anthropomorphic heart phantom demonstrates the clinical relevance of the increased spatial resolution with 16-slice CT acquisition (Fig. 6). The model

includes contrast-enhanced coronary arteries containing stents and atherosclerotic plaques of known dimensions and categories. Data sets from 16-slice scanners can be reconstructed with different image widths for optimization of the trade-off between spatial resolution and signal-to-noise ratio for specific clinical applications. For 16 × 0.75-mm collimation, slices with a thinnest possible image of 0.8 mm can be generated, thus allowing for substantially improved visualization of coronary artery lumen compared to 4-slice CT.

CLINICAL IMAGING PROTOCOLS The optimal scan technique for a given clinical application very much depends on the desired spatial and contrast resolution for that application. Prospective ECG triggering can be readily used for contrast-enhanced imaging of great-vessel morphology within limited scan ranges and for non-contrastenhanced detection of coronary calcification with low radiation exposure. Nevertheless, retrospective ECG gating has been shown to be useful for quantification of coronary calcium with improved reproducibility owing to reconstruction with overlapping images and shorter scan times (31). Contrast-enhanced visualization of small cardiac morphology and the coronary arteries with the best possible spatial and temporal resolution, as well as complete coverage of the cardio-thoracic vasculature, is feasible only with retrospectively ECG-gated scan acquisition. With 4-slice CT scanners and retrospectively ECGgated spiral scanning, a true 3D data set of the cardiac and coronary anatomy can be acquired with 0.6 × 0.6-mm in-plane resolution and 1.0-mm longitudinal resolution based on 4 × 1-mm slice collimation. A 10–12-cm scan range can be covered in a 30–40-s breath-hold time using 1-mm slices. The

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Fig. 6. An anthropomorphic numerical heart and coronary artery phantom was used to evaluate the influence of spatial resolution and slice width on visualization of coronary artery lumen and coronary plaque. The contrast enhanced left coronary artery segments (enhancement 250 HU) contain plaques with different properties and a stent in the proximal left anterior descending (LAD) coronary artery: lipid plaque 30HU, fibrous plaque 80 HU, calcified plaque 500 HU, and a stent with 50% in-stent lumen narrowing caused by a lesion with 30 HU (A). 16-slice CT with 16 × 0.75-mm collimation allows for retrospective reconstruction of different slice thicknesses between 0.8 mm and 3.0 mm (B). The phantom was reconstructed with 1.3-mm (C), 1.0-mm (D), and 0.8-mm (E) slice width, and the proximal LAD was displayed with multiplanar reformations. Differentiation of the lesions and visualization of in-stent lumen is possible with slice width ⱕ1.0 mm.

subsequent introduction of 8-slice CT scanners has reduced breath-hold times by about a factor of two, but this is still too long for routine submillimeter slice scanning. Most recently, 16-slice CT scanners provide improved longitudinal resolution with submillimeter collimation (0.5–0.75 mm) and improved in-plane spatial resolution of 0.5 × 0.5 mm. Despite thinner slices, breath-hold times can be reduced to 15–20 s for a 12-cm scan range owing to simultaneous acquisition of 12–16 detector slices (24). Diagnostically adequate image quality should be provided at the minimum radiation exposure possible. Therefore, scan protocols have to be developed for different applications with optimized image quality, spatial resolution, and radiation exposure. Various publications are available that discuss the radiation exposure of MSCT in cardiac applications (32,33). The calculation of patient dose from CT examinations has become more complex since the introduction of multislice scanners. Not only is dose related to tube current and voltage and exposure time, but also to slice thickness and helical/ spiral pitch. Thus, different exam protocols, as developed by

different institutions and manufacturers, may have widely varying dose consequences. The estimations of the effective patient dose values in Table 1 (34) are based on calculations of the generally available computer program WinDose (35) that have been validated with phantom measurements (36). It should be kept in mind that programs such as WinDose calculate effective dose to a mathematical phantom, and the dose to individual patients will vary depending on their size and weight, as well as the specific protocols used. For the detection and quantification of coronary artery calcium, contrast enhancement is generally not used, although accurate measurement of coronary calcium is also feasible using the thin-slice CT angiography protocol (37). For coronary CT angiography, the contrast medium injection must be carefully tailored by either using a test bolus or automatic bolus triggering technique. Since scan times for imaging of the heart on modern 4-, 8-, or 16-slice CT scanners range from 15 to 40 s, 80 to 150 mL of contrast medium at injection rates between 3 and 5 mL/s is needed to maintain homogenous vascular opacification throughout the scan. Saline chasing has proven manda-

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Table 1 Cardiac CT Scan Protocols With 4-Slice and 16-Slice CT ECG-trigger (Ca-Score)

Scan range [mm] Collimation per slice [mm] Image thickness [mm] Rotation Time [ms] Table Feed kv/mA Eff. Dose [mSv], (No ECG Modulation) Eff. Dose [mSv], Male/Female (ECG-Modulation)

ECG-gating (Ca-Score)

ECG-gating (High-Res)

4-Slice CT

16-Slice CT

4-Slice CT

16-Slice CT

4-Slice CT

16-Slice CT

120 2.0–3.0 3.0 500 8–12 mm/scan 120/100

120 1.0–3.0 3.0 370–500 16–24 mm/scan 120/100

120 2.0–2.5 3.0 500 6–7.5 mm/s 120/100

120 1.0–2.0 3.0 370–500 12–16 mm/s 120/100

100 1.0–1.25 1.3–1.5 500 3–4 mm/s 120/300

100 0.5–1.0 0.6–1.25 370–500 5–8 mm/s 120/400

Male/Female approx 0.6/1.0

approx 0.5/0.8

approx 2.0/3.0

approx 1.8/2.7

approx 6.0/9.0

approx 8.0/10.0

n.a.

n.a.

approx 1.2/1.6

approx 1.2/1.6

approx 3.5/5.5

approx 5.0/6.5

tory for reduction of the volume of contrast medium needed for consistently high vascular enhancement. This also helps in avoiding streak artifacts, which frequently arise from dense contrast material in the superior vena cava and the right atrium and sometimes interfere with the interpretation, especially of the right coronary artery. Techniques for contrast bolus optimization have been developed in the past (38,39) but have not been widely used, since reasonable results could be obtained by adapting single-slice CT strategies for contrast administration to dual- and 4-slice scanners. However, the introduction of ever-faster CT acquisition techniques now requires careful custom tailoring of the bolus for achieving adequate and consistent contrast medium attenuation within the cardiovascular system.

CLINICAL APPLICATION QUANTIFICATION OF CORONARY CALCIFICATION

EBCT has been established as a noninvasive imaging modality for the detection and quantification of coronary calcium by using the Agatston-scoring algorithm (2). With EBCT scanning, typically 3-mm thick slices are acquired contiguously with prospective ECG triggering in mid-diastole and an exposure time of 100 ms per slice. An effective dose of about 0.9 mSv was reported for this protocol (40). A known limitation of coronary artery calcium scoring with EBCT is the high interscan variability associated with the technique (41). This high variability has limited the usefulness of coronary artery calcium measurements for tracking the progression of atherosclerosis with time or for patients undergoing statin (lipid-lowering) therapy, which may become a potentially powerful future application of this technique (42). Since the introduction of sub-second gantry rotation, imaging of coronary artery calcium has also been evaluated with single-slice (4) and dual-slice mechanical CT (43). Owing to increased imaging performance in terms of temporal resolution and volume coverage, MSCT can be expected to provide coronary calcium quantification with substantially higher accuracy and better reproducibility than mechanical single- and dualslice CT (31,40). Optimal acquisition techniques have to be

developed, and Ca-scoring data acquired with MSCT need careful clinical evaluation and comparison to EBCT results. Both ECG-triggered sequential and ECG-gated helical/spiral scanning can be used to acquire calcium-scoring data. Scanning is performed without contrast enhancement in a cranio-caudal direction from the top of the pulmonary artery trunk to the apex of the heart (roughly a 12-cm scan range). A 3-mm slice width is routinely used for EBCT scanning, as it represents the thinnest slice width that allows for a single breath-hold scan. 4-, 8-, and 16-slice CT scanners generally use slice widths of 2.0 to 3.0 mm as the closest match to the standard EBCT protocols. A tube voltage of 120 kV is recommended, as it provides the best relation of contrast-to-noise ratio and radiation exposure. For most MSCT scanners, 100 mA tube current is adequate to achieve sufficiently high signal-to-noise levels to detect small calcified lesions. The tube current may need to be increased for large patients (e.g., to 150 mA) to maintain a diagnostic signal-to-noise level at the expense of increased radiation exposure. ECG-triggered scanning allows the scan volume to be covered in 20–25 s with 4-slice CT scanners and in 10–15 s with 8- and 16-slice CT scanners. The effective patient dose is about or less than 1 mSv (see also Table 1). Since the newer scanners acquire multiple contiguous slices simultaneously, the likelihood of slice misregistration in the z-axis is less than in the case of single-slice scanners. This, together with the reduced breathhold time, suggests that multislice scanners will be the preferred modality for this examination. Comparative studies of EBCT and prospectively ECG-triggered MSCT were able to demonstrate good measurement agreement in phantom experiments (31) and high correlation in patient studies (40,44,45). However, a high mean interexamination variability of 22–32%, comparable to the interexamination variability of two consecutive EBCT examinations, is common with prospectively ECGtriggered MSCT, owing to the presence of motion artifacts and misregistration between the sequential acquisitions. ECG-gated spiral scanning provides shorter breath-hold times as compared to ECG-triggered scanning, as well as more consistent volume coverage based on overlapping images. A

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Fig. 7. Different scan protocols for 4- and 16-slice CT were compared in a phantom study to investigate the sensitivity for the detection of small amounts of coronary calcification. The phantom consisted of a Lucite cylinder embedded in an anthropomorphic chest phantom with inserts of different concentrations of calcium hydroxylapatite (Ca HA) and different diameters (200, 400, and 800 mg/cm3 Ca HA) (A). Slices with 3-mm slice width were reconstructed based on scan data acquired with 133 mAs and 4 × 2.5-mm, 16 × 1.5-mm, and 16 × 0.75-mm collimation (SOMATOM Sensation 4 and SOMATOM Sensation 16, Siemens). The smallest calcifications (1 mg mass, arrows) can be detected only with the 16 × 0.75-mm protocol. A case study performed with 16-slice CT and 16 × 1.5-mm collimation reveals small calcifications in the middle segment (B) and in the distal segment (C) of the right coronary artery (case study courtesy of the Department of Radiology, Grosshadern Clinic, University of Munich, Germany).

12-cm scan range can be completed in 15–20 s with 4-slice CT and in 6–10 s with 8- and 16-slice CT. The spiral interpolation algorithms generate 3-mm thick images (full width at half maximum) based on a slice thickness of 2.0 to 2.5 mm for 4- and 8-slice CT scanners and 1.25–2.0 mm for 16-slice CT scanners (see also Table 1). Optimal detection accuracy of small calcified lesions might be achieved with 16-slice scanners via reconstruction of 3-mm thick images from scan acquisition with submillimeter collimation (46). Retrospectively ECG-gated spiral/helical scanning represents the preferred scan technique for minimized inter-examination variability. Recent independent studies found interscan variability of about 10% or less for repeat 4-slice CT scanning (31,47,48), which may be accurate enough to detect significant changes in the total atherosclerotic disease burden in patients with and without specific therapy. Interscan variability may be further improved with the latest 16-slice CT scanners, primarily based on faster rotation time and increased scan speed (Fig. 7). In comparison to prospectively ECG-triggered technique, the drawback to using retrospective ECG gating is higher patient dose. Frequently, healthy, asymptomatic individuals undergo coronary calcium scoring

in the context of screening. Especially in this population it is imperative to limit radiation dose to a minimum. This can be achieved by properly adapting scan protocols (49), or by using sophisticated technical developments such as ECG-based tube current modulation (28), which can decrease effective radiation exposure of the patient by as much as 50% (28). The modulation transfer function of the convolution kernel that is used for image reconstruction has considerable influence on in-plane spatial resolution and signal-to-noise ratio, and thus can seriously affect quantitative measurements. For coronary calcium scanning, a medium-sharp convolution kernel is used that provides moderate image noise for low radiation exposure and about 0.6 × 0.6-mm in-plane resolution (approx 4 line pairs (lp)/cm at 50% and 9 lp/cm at 2% MTF). Edge enhancement from a sharp kernel should be avoided, as it may lead to an overestimation of scores and to misleading artifactual lesions at the pericardium close to the coronary arteries. The traditional method for calculating calcium scores is that described by Agatston (2). Recent studies describing better results for interscan and for inter- and intra-observer variability strongly suggest that truly quantitative approaches may offer

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Fig. 8. Presentation of the platform used for quantification of coronary calcification (syngo Calcium Scoring, Siemens). Lesions exceeding the calcium threshold of 130 HU are identified with 3D-based picking and viewing tools, and are assigned to the different coronary arteries (left main, left anterior descending, circumflex, and right coronary arteries). Coronary calcifications are quantified my means of Agatston score, calcium volume, and calcium mass. Calibration factors that are predetermined with phantom measurements and that depend on the scan protocol are the basis for calculation of calcium mass. The quantitative measurements are displayed and reported in table format.

significant advantages over the Agatston scoring method (31,47,48). The new methods include both a measurement of lesion volume (but without the arbitrary weighting factor used in Agatston scoring) and calculation of calcium mass. Advanced software platforms (Fig. 8) allow for assessment of equivalent volume and total calcified plaque burden in terms of absolute calcium mass, based on actual scanner-specific calibration factors (47,48). The latter technique probably has the greatest potential to increase accuracy, consistency, and reproducibility of coronary calcium assessment (50), and thus may replace traditional scoring methods in the near future (51). CARDIAC AND CORONARY CT ANGIOGRAPHY

The image requirements for noninvasive coronary CT angiography are high spatial resolution, low-contrast detectability, and temporal resolution. In addition to scanner performance, image quality depends on various patient parameters, and optimization of examination protocols is critical for reliable diagnostic studies.

Cardiac and coronary CT imaging with MSCT requires ECG-gated thin-slice spiral scan protocols with table speed determined by the patient’s heart rate in order to ensure complete phase-consistent coverage of the heart with overlapping images. Most MSCT scanners provide scan protocols with overlapping helical/spiral pitches between 0.2 and 0.4 that enable gapless volume coverage for heart rate higher than approx 40/min. The helical/spiral pitch is defined as the table feed per gantry rotation divided by the X-ray beam width (equal to slice width multiplied by the number of slices). Usually, the cranio-caudal size of the heart to be covered by the scan is in the range 10–12 cm. Four-slice CT scanners with 500 ms rotation time and slice thickness of 1.0–1.25 mm can cover the entire heart during a 30–40-s breath-hold. With 8-slice CT scanners, the breath-hold time can be reduced to 20–25 s with the same spatial and temporal resolution. Recent 16-slice CT scanners provide high-resolution cardiac scan protocols with submillimeter slice collimation (0.5–0.75 mm) and in-plane

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Fig. 9. Coronary CT angiography examination of a patient with suspected coronary artery disease (A) using a 16-slice CT scanner in correlation with conventional coronary angiography (B). Scan protocol: 16 × 0.75-mm detector collimation, 1.0-mm reconstructed slice width, 420-ms rotation speed, 12-cm scan range covered in 16 s (SOMATOM Sensation 16, Siemens). Coronary CT angiography reveals high-grade stenosis in the proximal left descending coronary artery near the bifurcation of the first diagonal branch (arrow, 90% stenosis) and in the middle segment of the left descending coronary artery next to the bifurcation of the second diagonal branch (double arrow, 70% stenosis). Both lesions are confirmed by coronary angiography (case courtesy of Dr. C. S. Soo, HSC Medical Center, Kuala Lumpur, Malaysia).

Fig. 10. Coronary CT angiography examination of a patient who presented with chest pain in the emergency room, using a 16-slice CT scanner. Scan protocol: 16 × 0.5-mm detector collimation, 0.6-mm reconstructed slice width, 400-ms rotation speed, 12-cm scan range covered in 32 s (Aquillion 16, Toshiba). Visualization with maximum intensity projection reveals a significant amount of noncalcified plaque and moderate lumen narrowing in the proximal left descending coronary artery (A, arrow) and a high-grade lumen obstruction in the right coronary artery (B, double arrow) (case courtesy of Dr. H. Anno, Fujita Health University, Japan).

spatial resolution up to 0.5 × 0.5 mm (52,53). The image reconstruction protocols are adapted to the clinical priorities. As a result of the factors described above, accurate imaging of small coronary vessels with 4-slice scanners is limited. An important part of the scan protocol involves patient preparation. Patients should practice breath-holding for the expected duration of the scan so that they are well prepared. A short period of oxygen breathing prior to the procedure can also help patients extend

their breath-hold period. These precautions are particularly important when scanning with systems of 4 or 8 slices. With 16slice CT scanners and submillimeter collimation, usually slices not thinner than 1.0 mm are reconstructed, with 0.6 × 0.6-mm in-plane resolution to achieve optimal contrast resolution for assessment of coronary narrowing and intraluminal lesions (Figs. 9 and 10). Special algorithms with image width of less than 1 mm and in-plane resolution of 0.5 × 0.5 mm can be

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Fig. 11. Coronary CT angiography examination of a patient after percutaneous transluminal coronary angioplasty with stent in the distal right coronary artery, using a 16-slice CT scanner. Scan protocol: 16 × 0.75-mm detector collimation, 0.75-mm reconstructed slice width, 420-ms rotation speed, 12-cm scan range covered in 16 s (SOMATOM Sensation 16, Siemens). The patient presented for follow-up examination after the intervention and was examined to rule out re-stenosis. Coronary CT angiography reveals a patent stent lumen (arrow) but calcified and noncalcified atherosclerotic lesions and high-grade lumenal narrowing of about 70% proximal to the stent (double arrow). (A) The lumenal narrowing can be readily displayed with 3D volume-rendering technique in combination with cut planes that remove overlying anatomy. (B) Multiplanar reformation allows for visualization of the open in-stent lumen and of the narrowed lumen proximal to the stent. (C) Additional display of the same anatomy with maximum intensity projection provides clear assessment of the calcified and noncalcified atherosclerotic lesions related to the stenotic lesion. (D) Conventional angiography confirms the patent stent and the 70% stenosis, which was successfully dilated in the same session (case courtesy of Dr. C. S. Soo, HSC Medical Center, Kuala Lumpur, Malaysia).

applied for high-resolution reconstruction of small high-contrast structures (e.g., coronary stents and calcified coronary segments) in a limited range (Figs. 11 and 12). Rotation times down to 370 ms and the extended number of slices, up to 16, result in a reduced scan time of 15–20 s (see also Table 1). Thus, 16-slice CT can also cover larger scan ranges of 18–20 cm with ECG-gated thin-slice spiral scan protocols in a reasonably short breath-hold of 25–30 s that enables high-resolution imaging of most parts of the great thoracic vasculature and coronary bypass grafts over their entire course (Fig. 13). Optimization of scan protocols in terms of radiation exposure is particularly important for contrast-enhanced CT imaging of the coronary arteries. Sufficiently high spatial resolution and low-contrast resolution has to be achieved in patients of all sizes at the lowest possible radiation exposure. For tube voltage of 120 kV and 500 ms rotation time, tube current of approx 300 mA should be used for imaging 4- and 8-slice CT with slice width of 1 to 1.25 mm. The tube current may need to be increased to approx 350–400 mA for 16-slice CT using submillimeter slices and faster rotation time. ECG-gated scan acqui-

sition with highly overlapping helical/spiral pitch (i.e., pitch much less than 1) in a 10-cm scan range results in an effective dose of approx 7–8 mSv for males and approx 9–11 mSv for female patients (based on protocol examples in Table 1). Despite increased tube current and spatial resolution with 16-slice CT scanners, radiation exposure does not considerably increase, due to better dose utilization of 16-slice detector geometry (16,17). However, radiation exposure increases with reduced spiral pitch and with extension of the scan range. Using ECG-gated dose modulation, radiation exposure can be reduced by 30–50% depending on heart rate, provided that images do not need to be reconstructed over a wide range of the RR interval. ECG-gated dose modulation can reduce radiation exposure to approx 3.5–6.0 mSv for male and to approx 4.5–8.0 mSv for female patients, and works best in patients with a reasonably stable heart rate during the scan. The overall diagnostic quality of coronary CT angiography largely depends on choice of the appropriate reconstruction time point within the cardiac cycle, the rate and stability of the patient’s heart rate during the examination, and the effectiveness of contrast enhancement. The motion pattern of the left

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Fig. 12. Coronary CT angiography examination of a patient after percutaneous transluminal coronary angioplasty with two stents in the left descending coronary artery using a 16-slice CT scanner. Scan protocol: 16 × 0.5-mm detector collimation, 0.6-mm reconstructed slice width, 400-ms rotation speed, 12-cm scan range covered in 32 s (Aquillion 16, Toshiba Medical). Cross-sectional reconstruction of orthogonal multiplanar reformations and longitudinal visualization of the vessel based on automatic center-line detection and data segmentation shows both stents open (Vessel Probe, Vital Images) (case courtesy of Dr. Strobie, Florida Institute for Advanced Diagnostic Imaging).

heart and the left anterior descending and circumflex coronary arteries follows the left-ventricular contraction, whereas the right coronary artery moves synchronously with the right heart, i.e., the right atrium. Because of these different motion patterns, different reconstruction time points over the cardiac cycle are frequently necessary in order to display the different coronary vessels with a minimum of motion artifact (26,27). Most studies agree that patient heart rate is inversely related to image quality of cardiac and coronary CT angiography (12–14,26,27) because of motion artifacts. It has been shown that MSCT provides better diagnostic accuracy and reliability of results in patients with slow heart rates. Study data based on 4-slice CT with 500-ms rotation time indicates that an upper limit to achieve consistently appropriate image quality lies between 65 and 75 beats per minute (bpm) (26,27). At higher heart rates, adequate image quality can be achieved by using segmented image reconstruction, but overall results may be less consistent and reproducible. Even with the recent reduction of gantry rotation times to as little as 370 ms (Fig. 14), heart rate still remains the crucial factor in determining motion artifact and thus image quality. In those patients with heart rates above the 75–80 bpm threshold, the practical options are use of segmented reconstruction to improve temporal resolution where possible, or reduction of the heart rate pharmacologically by administering beta-blockers. Reliable evaluation of larger cardiac morphol-

ogy, such as the cardiac chambers and the great vessels, is possible in patients who present with higher heart rates without resorting to drugs, although some image artifacts may be present. The reliability of multislice cardiac and coronary CT angiography in patients with arrhythmias is limited. However, misinterpretations of the ECG signal can be partially compensated by retrospective editing of the ECG trace. Persistent irregular heart rates, such as in patients with atrial fibrillation, are contraindications for coronary CTA, but the assessment of the greater cardiac morphology such as the ventricles and atria usually remains possible. The presence of heavy coronary calcification may limit the value of CT coronary imaging, because beam hardening and partial volume effects, and an inability to distinguish between calcium and contrast, can completely obscure the coronary lumen. Metal objects such as stents, surgical clips, and sternal wires can also obscure the evaluation of underlying structures. Use of the thinnest possible slice width reduces partial-volume artifacts and improves visualization of calcified coronary segments. Additionally, dedicated filtering could be beneficial to the imaging of calcified vessels. Optimization of contrast media injection protocols for cardiac and coronary CT angiography is aimed at providing homogenous enhancement within the entire course of the coro-

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Fig. 13. Coronary CT angiography examination of two patients using a 16-slice CT scanner. with 16 × 0.75-mm detector collimation, 420-ms rotation speed, and extended volume coverage of 15 cm in order to visualize the heart, the ascending aorta, and the pulmonary vessels (SOMATOM Sensation 16, Siemens). (A) The first case demonstrates abnormal anatomy of the left descending coronary artery, including multiple fistula. Real-time 3D rendering is of advantage for assessment of the complex anatomy conditions. (B) In the second case, three bypasses to right coronary artery, left anterior descending coronary artery, and marginal branch are visualized with 3D volume-rendering technique. The bypass to the left anterior descending coronary artery (arrow) shows a patent proximal and distal anastomosis. However, a 50% stenosis (arrow head) is present in the proximal part of the bypass. The other two bypasses reveal open lumen over the entire course (cases courtesy of Dr. G. Lo, Department of Radiology, Hongkong Sanatorium Hospital [A] and the departments of Radiology and Cardiology, RhönKlinikum Bad Neustadt, Germany [B]).

nary arteries in order to facilitate density-threshold-dependent 2 and 3D visualization. Contrast attenuation within the vessel should be high enough to allow for lesion detection, but not high enough to obscure calcified coronary artery wall lesions. Adequate opacification can be achieved in the majority of patients over the course of a 40-s scan with 140 mL of 300 mg/mL iodinated contrast material injected at a flow rate of 3.5 mL/s. Owing to increased acquisition speed with 16-slice CT (approx 20 s scan time) the amount of contrast media can be reduced to 80–100 mL, but the injection rate will need to be increased to 4 to 5 mL/s. The use of reliable contrast-tracking software remains the best option for achieving the desired opacification Fig. 14. (left) Coronary CT angiography examination to rule out coronary artery disease using a 16-slice CT scanner. Scan protocol: 16 × 0.75-mm detector collimation, 1.0-mm reconstructed slice width, 370-ms rotation speed, 12-cm scan range covered in 16 s (SOMATOM Sensation 16 Cardiac, Siemens, Germany). Display of the coronary tree with 3D volume-rendering technique in combination reveals all main coronary segments normal. Also the rapidly moving right coronary artery can be displayed free of motion owing to the fast rotation speed (case courtesy of Department of Cardiology, University of Erlangen, Germany).

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Fig. 15. CT angiographic examination of a patient with an occlusion of the left anterior descending coronary artery using a 16-slice CT scanner. Scan protocol: 16 × 0.75-mm detector collimation, 1.0-mm reconstructed slice width, 420-ms rotation speed, 12-cm scan range covered in 16 s (SOMATOM Sensation 16, Siemens). In addition to reconstruction of the coronary artery tree, ECG-gated spiral image reconstruction was performed in 10 different time points during the cardiac cycle with a distance of 10% of the RR interval to provide input data for cardiac function evaluation. End-diastolic volume and end-systolic volume of the left ventricle as well as ejection fraction can be readily assessed based on short axis and long axis multiplanar reformations with 5-mm thickness that are loaded into a dedicated functional evaluation software (syngo Argus, Siemens) (case courtesy of the Department of Radiology, Tübingen University, Germany).

in patients with a wide range of cardiac output. Use of saline chasing technique (e.g., with a bolus of 50 mL of saline injected immediately after the iodine bolus) may be helpful for better contrast bolus utilization and for reducing streak artifacts arising from dense contrast material in the superior vena cava and the right heart. In order to minimize the likelihood of the latter effect, the injection site should be considered carefully. Thorough patient preparation remains an integral part of achieving consistent results. EVALUATION OF CARDIAC FUNCTION

In addition to the diagnosis of cardiac and coronary morphology, evaluation and quantification of cardiac function provides important information for the assessment of cardiac and coronary diseases. Because ECG-gated helical/spiral scanning

permits retrospective reconstruction of images at all phases of the cardiac cycle, it is a relatively simple matter to automatically segment the chamber and generate left-ventricular ejection fractions and wall motion using the same data set collected for coronary CTA. Thus, the diagnosis of cardiac and coronary morphology and also of basic cardiac function parameters can be derived from a single contrast-enhanced ECG-gated spiral examination with thin-section acquisition. Standard analysis techniques yield most of the metrics associated with cardiac function, including ejection fraction, end-diastolic and endsystolic volumes, stroke volume, and cardiac output. Left-ventricular regional function can also be quickly displayed on polar maps of percent wall thickness, wall motion, and ejection fraction (Figs. 15 and 16).

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Fig. 16. Cardiac Function Analysis software (Toshiba Medical Systems) reconstructs short- and long-axis images of the heart at multiple phases of the cardiac cycle. From this data set, ejection fraction, cardiac output, wall motion, and other parameters are calculated and displayed. This provides additional diagnostic information without any additional radiation to the patient (case courtesy of Dr. Shapiro, Johns Hopkins University, Baltimore).

First study results (54) show that basic cardiac function parameters derived with 4-slice CT correlate well with the goldstandard techniques MRI and coronary angiography, based on a standardized heart phase selection for end-diastolic and endsystolic CT reconstruction and semi-automated evaluation tools (Figs. 15 and 16). Although dose is significantly reduced during end diastole and systole with ECG-controlled tube current modulation, sufficient contrast resolution can still be obtained for functional evaluation. Use of MPRs in short and long heart axis with thickness of 5–8 mm enables appropriate delineation of the ventricle wall in both end-diastolic and end-systolic reconstruction. Automated direct 3D reconstruction of oblique planes in predefined views such as short and long heart axis and in multiple phases of the cardiac cycle will enable a more efficient workflow for cardiac function analysis in the future.

Rapid cardiac motion during the systolic phase of the cardiac cycle can cause motion artifacts in the end-systolic reconstructions. However, correct delineation of the ventricle walls is usually still possible with sufficient accuracy. The latest 16-slice CT scanners have the potential to further improve the accuracy of cardiac function measurement as compared to 4- and 8-slice CT scanners, based on increased gantry rotation speed. CARDIO-THORACIC IMAGING

Thoracic CT studies are frequently degraded by motion artifacts caused by transmitted cardiac pulsation. Typical diagnostic pitfalls related to this effect are false-positive findings of aortic dissection and distortion of paracardiac lung segments. Suppression of cardiac pulsation artifacts improves image quality in CT studies of the thorax, including the heart. Important indications are the planning and follow-up of surgical proce-

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Fig. 17. Electrocardiogram (ECG)-gated examination of the thoracic aorta in a 30-s breath-hold using a 16-slice CT scanner with 16 × 0.75-mm detector collimation and 420-ms rotation speed. The thoracic vasculature is displayed with 3D volume-rendering technique. Based on ECG-gated reconstruction that suppresses cardiac pulsation, the entire thoracic aorta can be evaluated free of pulsation artifacts (case courtesy of the Department of Radiology, Cleveland Clinic Foundation, USA).

dures, diagnosis or exclusion of aortic dissection and aortic aneurisms, detection of pulmonary embolism, assessment of congenital heart and vessel disease, and early detection and reliable diagnosis of paracardiac lung nodules. Prospectively ECG-triggered and retrospectively ECGgated protocols have been successfully applied to suppress cardiac-related motion artifacts in thoracic studies. With 4-slice CT, ECG-triggered or ECG-gated thin-slice scanning of the thorax is usually not possible within a single breath-hold, but can be used for re-scanning that part of the thorax where most pulsation is present. With the substantial performance increase of 16-slice CT, retrospectively ECG-gated coverage of the thorax is feasible in a single breath-hold and with a single contrast injection (Fig. 17). Thus, this technique now has the potential to be used as a standard examination for multislice spiral examination of the lung and thoracic vasculature. As a future step, ECG-gated thoracic imaging may become possible even with submillimeter resolution owing to 16-slice CT in combi-

nation with specialized ECG-gated cone-beam reconstruction techniques that enable faster volume coverage (30).

FUTURE PERSPECTIVE Further CT technology enhancements are required for accurate and consistent diagnosis of cardiac and coronary diseases, including the detection and quantification of coronary artery stenosis and coronary atherosclerotic lesions. Detection and quantification of the degree of lumen narrowing with the ability to differentiate a 10–20% change in vessel cross-sectional area represents a future goal for cardiac CT imaging. To meet this goal, future CT systems need to achieve a spatial resolution in all three dimensions (isotropic voxels) of 0.4–0.5 mm for visualization of the main coronary vessels and 0.3 mm or better for smaller branches. A recent study indicates that a heart-rateindependent temporal resolution of 100 ms or less allows for virtual elimination of motion artifacts in phases of the cardiac cycle with limited motion, with heart rates up to approx 100

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Fig. 18. (A) Illustration of a prototype system with large-area detector technology, capable of acquiring 256 0.5-mm slices simultaneously (Toshiba Medical Systems). Experimental ex vivo and human studies demonstrate the potential of such future CT scanners to cover large patient volumes with a single gantry rotation. (B) The 3D scan of the chest demonstrates the potential for capturing the heart in one rotation (images courtesy of Y. Saito, Toshiba Medical Systems).

Fig. 19. The anthropomorphic heart and coronary artery phantom displayed in Fig. 6 was used to compare the maximum possible spatial resolution of 16-slice CT with future area detector CT systems (A) that may provide detector pixel sizes below 0.5 mm (CT prototype with flatpanel detector system, Siemens). Such systems may be able to cover the heart in a single scanner rotation with isotropic resolution of 0.25 mm. Extremely high spatial resolution can improve visualization of in-stent lumen and small coronary segments compared to 16-slice CT (B), but do not necessarily provide improved delineation of noncalcified coronary lesions because of compromised signal-to-noise ratio (C).

bpm (55). For motion-free imaging at very high heart rates and in phases with rapid cardiac motion for analysis of cardiac function, a temporal resolution of 50 ms or less might be required (56). Scan acquisition within a single, short breathhold is mandatory for minimized contrast-medium injection and to avoid respiratory artifacts. Breath-hold times of 15 s or less are appropriate for stable patients, but breath-hold times of 10 s or less are advisable for patients who are ill or uncooperative. Ideally, all data of the complete heart anatomy would be acquired within a single heart cycle or less without patient movement. All these requirements related to spatial resolution, temporal resolution, and scan time have to be achieved without

substantial increase of radiation exposure, which should not exceed the amount of invasive diagnostic coronary angiography. The very short acquisition times of EBCT, down to 50 ms, combined with prospectively ECG-triggered scanning, enable motion-free imaging of the coronary arteries for patients with moderate and higher heart rates and stable sinus rhythm. However, the restrictions in spatial resolution and contrast-to-noise ratio as well as rather long breath-hold times limit the ability of EBCT today to reliably visualize all main coronary artery segments and noncalcified atherosclerotic plaques. New EBCT detectors are under evaluation that allow for simultaneous acquisition of two 1.5-mm slices and increased in-plane spatial

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Fig. 20. CT/positron emission tomography (PET) examination of a patient with a known occlusion of the left anterior descending coronary artery and history of myocardial infarction (biograph Sensation 16, Siemens). The 3D volume-rendering reconstruction of the ECG-gated 16-slice CT scan reveals the occluded coronary vessel and a related infarct scar. The PET scan demonstrates a perfusion defect and necrotic myocardium at the anterior wall (case courtesy of the Department of Radiology of Tübingen University, Germany, and the Department of Nuclear Medicine of the Technical University of Munich, Germany).

resolution via finer structuring of the elements of the fixed detector ring. With these detectors, the heart can be scanned with 1.5-mm slices in a 30–40-s breath-hold. However, limited signal-to-noise ratio will remain a major challenge for EBCT technology for high-resolution cardiac and coronary artery imaging. The temporal resolution of current multislice mechanical CT scanners needs to be improved to provide motion-free and robust coronary imaging also for moderate and high heart rates. Since the introduction of CT in 1972, there has been a persistent and successful effort to reduce gantry rotation times, reaching a remarkable 0.4 . Further increased rotation speed is still a very real goal; however, the rotational forces on the gantry components (tube, generator, and detector) increase as the square of the rotation speed. Thinner slices, leading to improved z-axis resolution, are technically feasible, but require a higher radiation dose to maintain a high contrast-to-noise ratio, and more detector-slices to maintain a short scan time (<20s). As a complement to further increased spatial resolution, advanced beam-hardening and metal artifact reduction algorithms can be developed that improve imaging of calcified and stented coronary vessels; use of

these algorithms to date is restricted to cerebral and bone imaging. Practical cardiac imaging has also benefited tremendously from the development of advanced software, particularly with regard to image reconstruction. Another approach to improved temporal resolution may lie with advances in segmented image reconstruction. While current algorithms are robust, using as many as four cardiac cycles, these and related techniques may develop to further extend the range of patient heart rates that can reliably be imaged. Area detector technology and related new cone beam reconstruction techniques are being researched that may allow the entire coronary anatomy to be covered in a single heartbeat without movement of the table. Prototype systems with large area detectors exist, capable of acquiring as many as 256 slices of 0.5 mm simultaneously. Alternative designs can provide in-plane and through-plane spatial resolution even up to 0.2 mm using flat-panel detector technology (Figs. 18 and 19). With these CT scanners, imaging of high-resolution morphology as well as dynamic and functional information via repeated scanning of the same scan range may become possible. The application potential of such technology is being evaluated with

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experimental systems using phantom models and post mortem hearts. Initial experience shows that today’s area detector technology is still too limited in contrast resolution, and the high radiation dose that is needed to provide adequate signal-tonoise ratio even for high-contrast studies is unacceptable for use in human subjects. The latest MSCT scanners also allow combining 16-slice CT with PET cameras. These systems may allow for a clinical combination of cardiac CT imaging and cardiac PET scans in a single examination and subsequent fusion of the information on cardiac morphology and myocardial function and metabolism (Fig. 20). The clinical potential of these scanners is currently under evaluation, and initial study data can be expected in the near future.

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47. Ohnesorge B, Kopp AF, Fischbach R, et al. Reproducibility of coronary calcium quantification in repeat examinations with retrospectively ECG-gated multislice spiral CT. Eur Radiol 2002;12:1532–1540. 48. Moser K, Bateman T, Case J, et al. The influence of acquisition mode on the reproducibility of coronary artery calcium scores using multi-detector computed tomography (abstract). Circulation 2002(Suppl. II);106(19):II–479. 49. Hong C, Bae KT, Pilgram TK, et al. Coronary artery calcium measurement with multi-detector row CT: in vitro assessment of effect of radiation dose. Radiology 2002;225:901–906. 50. Ulzheimer S, Kalender WA. Assessment of calcium scoring performance in cardiac computed tomography. Eur Radiol 2003;13:484–497. 51. Becker CR, Schöpf UJ, Reiser MF. Coronary calcium scoring: medicine and politics. Eur Radiol 2003;13:445–447. 52. Nieman K, Cademartiri F, Lemos PA, et al. Reliable noninvasive coronary angiography with fast submillimeter multislice spiral computed tomography. Circulation 2002;106:2051–2054. 53. Ropers D, Baum U, Pohle K, et al. Detection of coronary artery stenoses with thin-slice multi-detector row spiral computed tomography and multiplanar reconstruction. Circulation 2003;107:664–666. 54. Juergens KU, Grude M, Fallenberg EM, Heindel W, Fischbach R. Using ECG-gated multidetector CT to evaluate global left ventricular myocardial function in patients with coronary artery disease. AJR Am J Roentgenol 2002;179:1545–1550. 55. Achenbach S, Ropers D, Holle J, et al. In-plane coronary arterial motion velocity: measurement with electron beam CT. Radiology 2000;216:457–463. 56. Wang Y, Watts R, Mitchell I, et al. Coronary MR angiography: selection of acquisition window of minimal cardiac motion with electrocardiography-triggered navigator cardiac motion prescanning—initial results. Radiology 2001;218:580–585.

CHAPTER 4 / ECG-TRIGGERED MSCT

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Image Reconstruction for ECG-Triggered and ECG-Gated Multislice CT THOMAS FLOHR AND TINSU PAN

INTRODUCTION

the limitations of established 4-slice/8-slice CT scanners, and first clinical studies have already demonstrated enhanced clinical performance (15,16). While system properties such as gantry rotation time and detector slice width determine the intrinsic temporal and spatial resolution of the data, dedicated scan and image reconstruction techniques are needed to optimize the outcome of cardiac CT examinations. In this chapter, we present the basics of ECG-triggered and ECG-gated MSCT scanning. We give an overview on image reconstruction techniques, starting with single-segment partial scan reconstruction and ending with multisegment approaches. We discuss the pros and cons of single- and multisegment reconstruction. We demonstrate the properties of reconstruction algorithms with patient scans, and end with a short summary and discussion.

Computed tomography (CT) imaging of the heart and the coronary anatomy requires high temporal resolution to avoid motion artifacts and to achieve sufficient spatial resolution— at best submillimeter—to adequately visualize small anatomical structures such as the coronary arteries. Furthermore, the complete heart volume has to be examined within the time of one breath-hold. First attempts to use single-slice spiral CT systems for cardiac scanning were not convincing because of poor temporal resolution and insufficient volume coverage with thin slices (1,2). Since 1999, 4-slice CT systems with higher volume coverage speed and improved temporal resolution thanks to faster gantry rotation (rotation time down to 0.5 s) have been clinically used for electrocardiogram (ECG)-triggered or ECG-gated multislice CT (MSCT) examinations of the cardiac anatomy (3–9). Coverage of the entire heart volume with thin slices (4 × 1-mm/4 × 1.25-mm collimation) within one breath-hold period became feasible, allowing for new applications such as high-resolution CT angiographies of the coronary arteries (6–9). First clinical studies have demonstrated the ability of MSCT to characterize lipid, fibrous, and calcified coronary plaques (10). Despite all promising advances, challenges and limitations remain for cardiac MSCT with 4-slice detectors. Spatial resolution is still not sufficient to clearly depict stents or severely calcified coronary arteries (6,7). Temporal resolution is not yet adequate for patients with higher heart rates, and a diagnostic outcome cannot be guaranteed in these cases despite careful selection of the reconstruction interval (11,12). The scan time of about 40 s required to cover the entire heart volume (approx 12 cm) with 4 × 1-mm, 4 × 1.25-mm collimation is at the limit for a single breath-hold scan. In 2000, a shorter scan time was realized with 8 × 1.25-mm collimation, cardiac MSCT, which enables scan times of about 20 s. In 2001, a new generation of MSCT systems was introduced. With simultaneous acquisition of up to 16 submillimeter slices and gantry rotation times down to 0.4 s, spatial resolution in the transverse direction and temporal resolution are further improved, while examination times are considerably reduced (13,14). Sixteen-slice systems have the potential to overcome

SCAN TECHNIQUES FOR ECG-CONTROLLED MULTISLICE CT: ECG-TRIGGERED AXIAL AND ECG-GATED SPIRAL SCANNING For ECG-synchronized examinations of the cardio-thoracic anatomy, either ECG-triggered axial scanning or ECG-gated spiral scanning can be used. The most basic approach is prospectively ECG-triggered axial scanning, which was previously introduced with electron beam CT. The patient’s ECG signal is monitored during examination, and axial scans are started with a predefined temporal offset relative to the R waves, which can be either relative (given as a certain percentage of the RR interval time) or absolute (given in ms), and either forward or reverse (5). Data acquisition is therefore “triggered” by the R waves of the patient’s ECG signal. A schematic illustration of absolute and relative phase setting is given in Fig. 1. The principle of ECG-triggered multislice axial scanning is illustrated in Fig. 2. The coordinate system in Fig. 2 shows the patient’s ECG-signal as a function of time on the horizontal axis and the position of the detector slices relative to the patient on the vertical axis (in this example, four detector slices are indicated). Usually, partial scan data intervals (180° + detector fan angle) are acquired. Thanks to optimized half-scan reconstruction algorithms with adequate data weighting, a temporal resolution up to half the gantry rotation time per image (250 ms for 0.5 s gantry rotation) can be achieved in a sufficiently centered region of interest. The number of images acquired with every scan corresponds to the number of active detector slices. In between the individual axial scans, the table moves to the next z position; the heart

From: Contemporary Cardiology: CT of the Heart: Principles and Applications Edited by: U. Joseph Schoepf © Humana Press, Inc., Totowa, NJ

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Fig. 1. Schematic illustration of absolute and relative phase setting for electrocardiogram (ECG)-controlled CT examinations of the cardiothoracic anatomy.

Fig. 2. Principle of electrocardiogram (ECG)-triggered multislice axial scanning. The patient’s ECG signal is indicated as a function of time on the horizontal axis. The position of the detector slices relative to the patient (four slices in this example) is shown on the vertical axis. Usually, partial scan data intervals (180° + detector fan angle) are acquired, which are marked as boxes.

volume is therefore covered in a “step and shoot” technique. As a result of the time necessary for table motion, only every second heart beat can be used for data acquisition, which limits the minimum slice width to 2.5 mm with 4-slice or 1.25 mm with 8-slice CT systems if the whole heart volume has to be covered within one breath-hold period. With retrospective ECG gating, the heart volume is covered continuously by a spiral scan. The patient’s ECG signal is recorded simultaneously to allow for a retrospective selection of the data segments used for image reconstruction. The principle of retrospectively ECG-gated spiral scanning is illustrated in Fig. 3. Similar to Fig. 2, the patient’s ECG signal is indicated as a function of time on the horizontal axis, and the position of the detector slices relative to the patient is shown on the vertical axis. The table moves continuously, and continuous spiral scan data of the heart volume are acquired. Only scan data acquired in a predefined cardiac phase, usually the diastolic phase, are used for image reconstruction (5,17). These scan data segments are indicated as boxes in Fig. 3. A variety of dedicated reconstruction approaches for ECG-gated spiral MSCT have been introduced with 4-slice CT scanners (3–5,17), resulting in a temporal resolution of half the gantry rotation time (250 ms for 0.5 s gantry rotation time) or better, thanks to multisegment

Fig. 3. Principle of retrospectively electrocardiogram (ECG)-gated spiral scanning. The patient’s ECG signal is indicated as a function of time on the horizontal axis, and the position of the detector slices relative to the patient is shown on the vertical axis. The table moves continuously, and continuous spiral scan data of the heart volume are acquired. Only scan data acquired in a pre-defined cardiac phase, usually the diastolic phase, are used for image reconstruction, which are marked as boxes.

reconstruction. Different from ECG-triggered axial scanning, scan data from every heart cycle can be used for image reconstruction; therefore, the entire heart volume can be covered with a 4-slice system within one breath-hold period using 1-mm or 1.25-mm slices. Image reconstruction during different heart phases is feasible by shifting the start points of the data segments used for image reconstruction relative to the R waves. For a given start position, a stack of images at different z positions covering a small subvolume of the heart can be reconstructed thanks to the multislice data acquisition (4,5,17). Prospective ECG triggering combined with “step and shoot” acquisition of axial slices has the benefit of smaller patient dose than ECG-gated spiral scanning, since scan data are acquired in the previously selected heart phases only. It does not, however, provide continuous volume coverage with overlapping slices, and misregistration of anatomical details cannot be avoided. Furthermore, reconstruction of images in different phases of the cardiac cycle for functional evaluation is not possible. Because ECG-triggered axial scanning depends on a reliable prediction of the patient’s next RR interval by using the mean of the preceding RR intervals, the method encounters its limitations for patients with severe arrhythmia. To maintain the benefits of ECG-gated spiral CT but reduce patient dose, ECGcontrolled dose-modulation has been developed (18). During the spiral scan, the output of the X-ray tube is modulated according to the patient’s ECG. It is kept at its nominal value during a user-defined phase of the cardiac cycle—in general, the mid- to end-diastolic phase. During the rest of the cardiac cycle, the tube output is reduced. Clinical studies with 4-slice CT systems have demonstrated dose reduction by 30–50%, depending on the patient’s heart rate, using ECG-controlled dose modulation (18).

IMAGE RECONSTRUCTION FOR ECG-TRIGGERED MULTISLICE AXIAL SCANNING Using prospective ECG-triggering, axial scan data are acquired. Since the table is stationary for each individual scan and moves only between scans, no multislice spiral interpolation is necessary. In general, partial scans are performed, with

CHAPTER 4 / ECG-TRIGGERED MSCT

Fig. 4. Geometry of CT data acquisition. A modern CT scanner acquires data in “fan beam geometry,” characterized by the projection angle α and by the fan angle β within a projection. Another set of variables serving the same purpose is θ and b. b denotes the distance of a ray from the iso-center. θ and b are the coordinates of a ray in “parallel geometry.”

a scan data segment covering 180° plus the detector fan angle (about 50–60°, depending on system geometry). Including some additional data for smooth transition weighting of complementary rays to avoid streaking artifacts resulting from data inconsistencies at the beginning and at the end of the scan interval, the total scan interval of a partial scan is ∆αp = 240– 260°. This is the minimum necessary for image reconstruction throughout the entire scan field of view (SFOV) of usually 50– cm diameter. The temporal resolution at a certain point in the SFOV is determined by the acquisition time window of the data contributing to the reconstruction of that particular image point. Similar to slice sensitivity profiles (SSP), temporal resolution may be characterized by time sensitivity profiles (TSP). The temporal resolution ∆Tima assigned to an image is the full width at half maximum (FWHM) of the TSP. In a conventional approach, the entire partial scan data segment is used for image reconstruction in any point of the SFOV. Redundant data are weighted using algorithms such as the one described by Parker (19). The temporal resolution ∆Tima in this case is ∆αp/360° times the rotation time of the scanner; for 0.5 s rotation, ∆Tima = 0.33–0.36 s. To improve temporal resolution, modified reconstruction approaches for partial scan data have been proposed (5,17), which are best explained in parallel geometry. A modern CT scanner acquires data in fan beam geometry, characterized by the projection angle α and by the fan angle β within a projection. Another set of variables serving the same purpose is θ and b. θ is the azimuthal angle and b denotes the distance of a ray from the iso-center (see Fig. 4). θ and b are used to label rays when projection data are in the form of parallel projections. A simple coordinate transformation relates the two sets of variables: θ = α + β, b = RFsinβ.

(1)

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Fig. 5. Sinogram illustrating parallel rebinning according to Eq. 1 for the partial scan data segment. The sinogram curves for three image points a, b, and c at different positions within the scan field of view are indicated.

Using this equation, the measured fan beam data can be transformed to parallel data, a procedure called “rebinning.” In parallel geometry, 180° of scan data are necessary for image reconstruction. For data acquisition in fan beam geometry, a partial scan interval larger than 180°, namely 180° plus the detector fan angle, is necessary to provide 180° of parallel data for any image point within the SFOV. In the center of rotation, for β = 0, 180° of the acquired fan beam data are sufficient to provide 180° of parallel data; see Eq. (1). If all redundant data are neglected, temporal resolution in the center of rotation can be as good as 180°/360° times the rotation time of the scanner; for 0.5 s rotation, ∆Tima = 0.25 s. As a consequence of the rebinning Eq. (1), data with different fan beam projection angles α and hence different acquisition times contribute to a parallel projection at projection angle θ. Fig. 5 is a sinogram and illustrates the rebinning procedure. Obviously, the temporal resolution is not constant, but depends on the position of the image point in the SFOV. This is illustrated in Fig. 5 for the example of three different image points a, b, and c. Measurement values contributing to point a in the iso-center are located on a straight vertical line in the sinogram (β = 0). Hence, the temporal resolution for this particular point is half the rotation time of the scanner. Data contributing to points b and c are located on sinosoidal curves in the sinogram. A measure for temporal resolution is given by the path lengths of the sinosoidal curves within the gray shaded parallel sinogram. Obviously, the total acquisition time of the data for point b is longer than for the central point a, whereas it is even shorter for point c. For clinical applications, the heart should be sufficiently centered within the SFOV to maintain a stable temporal resolution of half the gantry rotation time. It is not possible to make use of the areas

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Fig. 6. Spiral interpolation scheme for a four-slice scanner using one segment of multislice data for image reconstruction. The z position of the four detector slices changes linearly relative to the patient due to the constant spiral feed. The spiral interpolation is indicated for some representative projection angles α. Please note that in general no interpolation between projections measured at different projection angles, i.e., different acquisition times, is performed, even in cases where this would be possible (180°-type interpolation). On the bottom, the electrocardiogram signal is shown schematically.

with better temporal resolution, as start and end position of the X-ray source during ECG-triggered acquisition depend on the patient’s heart rate and cannot be fixed.

IMAGE RECONSTRUCTION FOR ECG-GATED MULTISLICE SPIRAL SCANNING Using ECG-gated multislice spiral scanning, the heart volume is covered continuously by a spiral scan. Image reconstruction for ECG-gated multislice spiral scanning therefore consists of two parts: multislice spiral interpolation to compensate for the continuous table movement and to obtain scan data at the desired image z position, followed by a partial scan reconstruction of the axial data segments as described above. A “single-slice” partial scan data segment is generated for each image using a partial rotation of the multislice spiral scan that covers the given z position. For each projection angle within the multislice data segment, a linear interpolation is performed between the data of those two detector slices that are in closest proximity to the desired image plane zima. The temporal resolution, which is limited to half the gantry rotation time for prospective ECG triggering, can be improved up to 1/(2N) times the rotation time by using scan data of N subsequent heart cycles for image reconstruction (17). With increased N, better temporal resolution is achieved, but at the expense of reduced volume coverage within one breath-hold time or loss of transverse resolution. To maintain good transverse resolution and thin-slice

images, every z position of the heart has to be seen by a detector slice at every time during the N heart cycles. As a consequence, the larger the N and the lower the patient’s heart rate, the more the spiral pitch has to be reduced. If the pitch is too high, there will be z positions which are not covered by a detector slice in the desired phase of the cardiac cycle. To obtain images at these z positions, far-reaching spiral interpolations have to be performed, which degrade SSPs and reduce transverse resolution.

SINGLE-SEGMENT RECONSTRUCTION At low heart rates, a single-segment reconstruction (N = 1) yields the best compromise between sufficient temporal resolution on the one hand and adequate volume coverage with thin slices on the other. For N = 1, consecutive multislice spiral data from the same heart period are used to generate the single-slice partial scan data segment for an image. The spiral interpolation scheme for a 4-slice scanner using one segment of multislice data is illustrated in Fig. 6, together with the calculation of the spiral interpolation weights for some representative projection angles. In general, no interpolation between projections measured at different projection angles, i.e., different acquisition times, is performed, even in cases where this would be possible (180°-type interpolation). The temporal resolution is constant and equals half the gantry rotation time of the scanner using optimized partial scan reconstruction techniques as described above. For 0.5-s gantry rotation time, temporal resolution is

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Fig. 7. Spiral interpolation scheme for a four-slice scanner using N = 2 subsegments of multislice data from consecutive heart periods for image reconstruction. Both subsegments have to fit together to build up a partial scan data interval. The spiral interpolation is indicated for some representative projection angles α.

∆Tima = 0.25 s. Some of the recently introduced 16-slice CT systems offer gantry rotation times even shorter than 0.5 s, such as 0.42 s or 0.4 s. In this case, temporal resolution can be as good as ∆Tima = 0.21 s or 0.2 s.

MULTISEGMENT RECONSTRUCTION At higher heart rates, temporal resolution can be improved by dividing the partial scan data segment used for image reconstruction into N = 2–4 subsegments acquired in subsequent heart cycles. Each subsegment is generated by using data from one heart period only, and there are temporal gaps between the multislice data segments used for image reconstruction. Similar to the case N = 1, for each projection angle α within subsegment j, a linear interpolation is performed between the data of those two detector slices that are in closest proximity to the desired image plane. The result are N single-slice partial scan subsegments located at the given image z position zima (see Fig. 7 for the example N = 2). With this technique, the patient’s heart rate and the gantry rotation time of the scanner have to be properly desynchronized to allow for an improved temporal resolution. Two requirements have to be met: firstly, start- and end-projection angles of the subsegments have to fit together to build up a full partial scan interval (see Fig. 8). As a consequence, the start projections of subsequent subsegments have to be shifted relative to each other. Secondly, all subsegments have to be acquired in the

same relative phase of the patient’s heart cycle to reduce the total time interval contributing to an image. If the patient’s heart cycle and the rotation of the scanner are completely synchronous, the two requirements are contradictory. For instance, for a heart rate of 60 beats per minute (bpm) and a 360° rotation time of 0.5 s, the same heart phase always corresponds to the same projection angle segment, and a partial scan interval cannot be divided into smaller subsegments acquired in successive heart periods. Then no better temporal resolution than half the gantry rotation time is achieved. In the best case, when the patient’s heart cycle and the rotation of the scanner are optimally desynchronized, the entire partial scan interval may be divided into N subsegments of equal length, and each subsegment is restricted to a data time interval of 1/(2N) times the rotation time within the same relative heart phase. Generally, depending on the relation of rotation time and patient heart rate, temporal resolution is not constant but varies between one half and 1/(2N) times the gantry rotation time. There are “sweet spots,” heart rates with optimum temporal resolution, and heart rates where temporal resolution cannot be improved beyond half the gantry rotation time. Multisegment approaches rely on a complete periodicity of the heart motion, and they encounter their limitations for patients with arrhythmia or patients with changing heart rates during examination. In general, clinical practice suggests the use of N = 1 segment at lower heart rates and N ≥ 2 segments at higher heart rates. In some CT scanners,

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Fig. 8. Schematic illustration of the two-segment cardio reconstruction approach. The circular graph represents the full partial scan interval in parallel geometry (180° of parallel data), which is composed of two subsegments acquired in subsequent heart cycles. These two subsegments have to be measured in the same phase of the cardiac cycle, and start- and end-projections have to fit together. To fulfill both requirements, the patient’s heart cycle and the rotation of the scanner have to be asynchronous.

the partial scan data segment is automatically divided into one or two subsegments depending on the patient’s heart rate during examination (Adaptive Cardio Volume ACV algorithm [17]). At heart rates below a certain threshold, one subsegment of consecutive multislice spiral data from the same heart period is used. At higher heart rates, two subsegments from adjacent heart cycles contribute to the partial scan data segment. In some other CT scanners, the single-segment partial scan images are reconstructed prospectively as baseline images, followed by a two-segment reconstruction retrospectively for a potential gain of temporal resolution for higher heart rates. Alternatively, a two-segment prospective reconstruction can be prescribed with a slower table feed for scanning the same cardiac anatomy in two heart cycles, followed by a retrospective single-segment reconstruction for comparison with the two-segment reconstruction. A single-segment reconstruction is usually preferred for its reliability, even though a two-segment reconstruction may yield a better image quality. Another approach is to prospectively adjust the rotation time of the scanner to the heart rate of the patient to obtain best possible temporal resolution for a multisegment reconstruction. The range of heart rates is preferred to cover 15 bpm for each selected gantry cycle, to account for the patient’s heart rate variation during a scan. Figure 9 shows an example of using 0.5-s and 0.6-s gantry rotation time for this implementation. The 0.5-s two-segment reconstruction covers low 60s to 75 bpm, followed by 0.6-s three- to four-segment reconstruction for 75–90 bpm, and 0.5-s three- to four-segment reconstruction for the heart rates of over 90 bpm. Figure 10 shows another example of using 0.42-s and 0.5-s gantry rotation time in combination with an automatic selection of one- and two-

segment reconstruction (ACV algorithm). The 0.5-s two-segment reconstruction covers 64–73 bpm, whereas the 0.42-s twosegment reconstruction is preferable for 73–90 bpm. Figures 11 and 12 show examples of patient scans at higher heart rates, to illustrate the potential of multisegment reconstruction to improve image quality in selected cases. Again, prospectively adapting the rotation time of the scanner and exploiting multisegment reconstruction requires a stable and predictable heart rate during examination and complete periodicity of the heart motion.

DISCUSSION AND SUMMARY We have reviewed the scanning and reconstruction techniques for ECG-controlled MSCT. Two basic scanning techniques are discussed: ECG-triggered axial scanning and ECG-gated spiral scanning. For ECG-triggered axial scanning, the X-ray will be turned on only for the duration of the data for image reconstruction; therefore, the dose to the patient can be kept to a minimum. For ECG-gated spiral scanning, the dose is higher, since the X-ray is turned on for the whole duration of the scanning. Ways of reducing the X-ray dose have been proposed, such as ECG-controlled dose modulation (18). There are two major reconstruction techniques associated with spiral scanning: one is single-segment reconstruction, where each image is reconstructed with the data from a single cardiac cycle; the other is N-segment reconstruction, where each image is reconstructed with the data from N contiguous cardiac cycles. The two-segment reconstruction has the advantage of extending from single-segment reconstruction without changing the gantry rotation cycle. The three- and four-segment reconstructions can be used when the heart rate is becoming too high (>75

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Fig. 9. A design of N-segment reconstruction with gantry cycles of 0.5 and 0.6 s to improve temporal resolution for higher heart rates. The 0.5-s two-segment reconstruction covers from the low 60s to 75 bpm, followed by 0.6-s three- to four-segment reconstruction for 75–90 bpm, and 0.5-s three- to four-segment reconstruction for heart rates of over 90 bpm.

Fig. 10. A design of automatic selection of single- and two-segment reconstruction (ACV algorithm) with gantry cycles of 0.42 and 0.5 s. 0.42-s gantry rotation is preferable for low heart rates (single-segment reconstruction) and for 73–90 bpm (two-segment reconstruction). The 0.5-s two-segment reconstruction yields better temporal resolution for 64–73 bpm.

bpm), and a slower gantry cycle of 0.6 s can be used to optimize the temporal resolution. Single-segment reconstruction is the clinically most robust reconstruction technique. The reliability of obtaining good quality images with N-segment reconstruction generally goes down when N becomes larger from 2, to 3, to 4. Multisegment reconstruction requires a stable heart rate during examination and complete periodicity of the heart motion. The cardiac MSCT has also benefited significantly from the advancements of 4 × 1-mm/4 × 1.25-mm to 16 × 0.75-mm/ 16 × 0.625-mm collimation and faster gantry speeds of 0.5 s to 0.42 s or 0.4 s. The wider coverage with thinner slices (16 × 0.75 mm/16 × 0.625 mm) has improved the spatial resolution

in the cranio-caudal direction (or Z coordinate) to submillimeter, with already submillimeter resolution in the in-plane direction (or X and Y coordinates); this is critical for coronary artery imaging, and has shortened the scan time of 40 s (4-slice) to 20 s (8- or 16-slice) or even 10 s (16-slice), which is well under a single breath-hold. The gantry rotation cycle of 0.5 s to 0.42 or 0.4 s has improved the temporal resolution of 0.25 s to 0.21 and 0.2 s, which will help the MSCT become a scanner for most patients. The image quality that can be obtained in clinical routine is demonstrated in Fig. 13. Meanwhile, first clinical experience has demonstrated the potential of 16-slice technology for cardiac imaging (15,16,20).

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Fig. 11. A patient study with heart rates of 97–101 bpm with three- to four-segment reconstruction. Shown here are the volume-rendered image, and the curved reformatted images of the left anterior descending (LAD), left circumflex (LCX), and right coronary artery (RCA). It demonstrates the potential for three- to four-segment reconstruction to improve the temporal resolution for higher heart rates.

Fig. 12. A patient study of heart rates of around 92 bpm with two-segment reconstruction. Shown here are the volume-rendered image, and a “spider view” maximum intensity projection showing the origins of left anterior descending, left circumflex, and right coronary artery (courtesy of Dr. Ropers, Erlangen University, Germany).

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Fig. 13. Case of a 68-yr-old male patient with a history of stroke secondary to a bilateral carotid obstruction. The CT scan was obtained on a 16-slice CT system. The images show severe calcification in the left anterior descending (LAD) and right coronary artery (RCA), as well as large pericardial calcifications. The calcifications are displayed in endoscopic and maximum intensity projection viewing techniques. Corresponding to the coronary angiogram, a 40% stenosis of the left main (LM) and 80% stenosis of the LAD and RCA were found (courtesy of Prof. Oudkerk, Groningen University, Groningen, the Netherlands).

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REFERENCES 1. Bahner M, Boese J, Lutz A, et al. Retrospectively ECG-gated spiral CT of the heart and lung. Eur Radiol 1999;9:106–109. 2. Kachelriess M, Kalender W. Electrocardiogram-correlated image reconstruction from subsecond spiral computed tomography scans of the heart. Med Phys 1998;25:2417–2431. 3. Kachelriess M, Ulzheimer S, Kalender W. ECG-correlated image reconstruction from subsecond multi-slice spiral CT scans of the heart. Med Phys 2000;27:1881–1902. 4. Taguchi K, Anno H. High temporal resolution for multi-slice helical computed tomography. Med Phys 2000,27(5):861–872. 5. Ohnesorge B, Flohr T, Becker C, et al. Cardiac imaging by means of electro-cardiographically gated multisection spiral CT—initial experience. Radiology 2000;217:564–571. 6. Achenbach S, Ulzheimer S, Baum U, et al. Noninvasive coronary angiography by retrospectively ECG-gated multi-slice spiral CT. Circulation 2000;102:2823–2828. 7. Becker C, Knez A, Ohnesorge B, Schöpf U, Reiser M. Imaging of non calcified coronary plaques using helical CT with retrospective EKG gating. AJR 2000;175:423–424. 8. Knez A, Becker C, Leber A, Ohnesorge B, Reiser M, Haberl R. Noninvasive assessment of coronary artery stenoses with multidetector helical computed tomography. Circulation 2000;101:e221–e222. 9. Nieman K, Oudkerk M, Rensing B, et al. Coronary angiography with multi-slice computed tomography. Lancet 2001;357:599–603 10. Schroeder S, Kopp A, Baumbach A, et al. Noninvasive detection and evaluation of atherosclerotic coronary plaques with multi-slice computed tomography. JACC 2001;37(5):1430–1435. 11. Hong C, Becker C, Huber A, et al. ECG-gated reconstructed multidetector row CT coronary angiography: effect of varying trigger delay on image quality. Radiology 2001;220:712–717.

12. Kopp A, Schröder S, Küttner A, et al. Coronary arteries: retrospectively ECG-gated multi-detector row CT angiography with selective optimization of the image reconstruction window. Radiology 2001;221:683–688. 13. Flohr T, Stierstorfer K, Bruder H, Simon J, Schaller S. New technical developments in multislice CT, part 1: approaching isotropic resolution with sub-mm 16-slice scanning. Fortschr Röntgenstr 2002;174:839–845. 14. Flohr T, Bruder H, Stierstorfer K, Simon J, Schaller S, Ohnesorge B. New technical developments in multislice CT, part 2: sub-millimeter 16-slice scanning and increased gantry rotation speed for cardiac imaging. Fortschr Röntgenstr 2002;174:1022–1027. 15. Kopp AF, Küttner A, Heuschmid M, Schröder S, Ohnesorge B, Claussen CD. Multidetector-row CT cardiac imaging with 4 and 16 slices for coronary CTA and imaging of atherosclerotic plaques. Eu Radiol 2002;12(Suppl 2):S17–S24. 16. Nieman K, Cademartiri F, Lemos PA, Raaijmakers R, Pattynama PMT, de Feyter PJ. Reliable noninvasive coronary angiography with fast submillimeter multislice spiral computed tomography. Circulation 2002;106:2051–2054. 17. Flohr T, Ohnesorge B. Heart rate adaptive optimization of spatial and temporal resolution for ECG-gated multi-slice spiral CT of the heart. JCAT 2001;25(6):907–923. 18. Jakobs TF, Becker CR, Ohnesorge B, et al. Multislice helical CT of the heart with retrospective ECG gating: reduction of radiation exposure by ECG-controlled tube current modulation. Eur Radiol 2002;12:1081–1086. 19. Parker D. Optimal short scan convolution reconstruction for fanbeam CT. Med Phys 1982;9(2):254–257. 20. Ropers D, Baum U, Pohle K, et al. Detection of coronary artery stenosis with thin-slice multi-detector row spiral computed tomography and multiplanar reconstruction. Circulation 2003;107:664–666.

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Phase-Correlated Image Reconstruction Without ECG MARC KACHELRIESS, PhD

AND

INTRODUCTION

WILLI A. KALENDER, PhD

the origin of the sync signal is not a property of the phasecorrelated reconstruction algorithm itself; it can be easily substituted by any other appropriate synchronization measure. There are several reasons to look into alternative synchronization approaches. Recording the ECG requires additional hardware and additional patient-handling effort. Further, extra systoles that do not necessarily correspond to cardiac motion are interpreted as valid signals and may therefore impair image quality in the reconstructions. Sometimes the ECG signal is corrupted due to hardware failure, is unavailable, or totally useless. A fallback solution is desired in such cases. Additionally, for some applications that may profit from cardiac motion reduction, such as thoracic imaging, applying the ECG leads is inconvenient or not desired.

Improvements in computed tomography (CT) technology such as the introduction of spiral CT, subsecond rotation times, and multislice data acquisition have stimulated cardiac CT imaging within the last decade (Fig. 1). Cardiac spiral CT started with the introduction of dedicated phase-correlated reconstruction algorithms for single-slice spiral CT in 1997 (1–3). These approaches have been generalized to the case of multislice spiral CT (MSCT) acquisition (2,4–6) to process data of 4-slice scanners. Since then, the algorithms have been extended to the case of cone-beam scanning with 16 slices (7–10) and to scanners with far more than 16 slices (11). Vendor-specific implementations that take into account the cone angle have not been announced yet. What all cardiac reconstruction algorithms have in common is the need to synchronize the reconstruction with heart motion. With this synchronization, the algorithms seek to use projection data from a temporal window (allowed data ranges) aligned to the synchronization points. The size of these allowed data ranges determines the temporal resolution of the reconstruction and thus the level of motion-artifact reduction. The position of the windows determines the motion phase that is visible in the reconstruction. The most elaborate phase-weighting strategy currently available is the cardio-interpolation (CI) method, which is an adaptive multiphase weighting: minimal-width allowed data ranges of all heart cycles contributing to a given z position are determined to form a 180° complete high temporal resolution data set ready for reconstruction. Inter-segment combination artifacts are eliminated by applying a multitriangular weighting function to each data segment followed by proper normalization. Other known methods such as singleand bi-phase weighting restrict the image contributions to one or two heart cycles, respectively, depending on the local heart rate, and are a subset of CI. The synchronization signal traditionally stems from the patient’s electrocardiogram (ECG), which is simultaneously recorded during the scan. In those cases, the reconstruction procedure is termed ECG-correlated reconstruction. Note that

KYMOGRAM DETECTION Recently, a hardware-independent synchronization method, the kymogram, has become available (12–14). The method in its present implementation consists of a raw data-based center of mass (COM) detection of the patient cross-section currently scanned. Since the heart is in permanent motion, the detected COM will vary with the tube position, and the synchronization information can be derived from these variations. The COM detection is illustrated in Fig. 2. The mathematical relations between object data and projection data state that the COM of the projection (at angle ϑ) of an object is equal to the projection (at angle ϑ) of the COM of the object. In our case this is illustrated with two small disks (Fig. 2A). The disk in the center of the heart is the patient’s COM. The second disk is the COM of the projection data. The positions of the disks are related by projecting along the ray direction. The kymogram algorithm uses the acquired raw data and computes the projection COM for each view angle ϑ. Then, adjacent projections are used to compute the intersection of the corresponding lines of COM projection and the current patient COM results (Fig. 2B). So far, the algorithm results in a COM curve similar to the plots on the right in Fig. 3. The curves are obscured by a dominant slowly varying bias; heart motion is not visible yet. The multiplanar reformations (MPRs) attached to the COM plots clarify the origin of the bias: the patient COM is dominated by large structures such as the overall thorax shape or the liver. As soon as the bias is removed (e.g., by subtracting a running mean of appropriate length), the cardiac motion is restored and

From: Contemporary Cardiology: CT of the Heart: Principles and Applications Edited by: U. Joseph Schoepf © Humana Press, Inc., Totowa, NJ

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Fig. 1. Four generations of spiral CT scanners. Collimation and rotation times (bottom) are given for typical CT coronary angiography protocols.

Fig. 2. (A) The center of mass (COM) of the current cross-section is projected onto the COM of the projection data. (B) Adjacent projection COMs can be used to find the object COM by simple intersection.

becomes visible. Figure 4 shows a plot of the unbiased heart COM motion. The dots’ hue values are chosen as the cardiac ECG phase (relative to RR). The fact that dots of similar color are located close together indicates a correlation of the heart’s COM and the ECG phase. For example, the upper right area corresponds to systolic, the lower left area to diastolic motion. The two-dimensional signal can now be reduced to a onedimensional function by projecting it onto the principal axis of cardiac in-plane motion (diagonal line in Fig. 4). An example of such a resulting kymogram function is given in Fig. 5. Visual inspection indicates a good correlation to the patient’s ECG except for regions at scan start and end that correspond to anatomical levels above and below the heart. In analogy to the ECG’s R peaks, the kymogram’s maxima are called K peaks,

and synchronization is performed with respect to the K peaks, just as it is done with the ECG’s R peaks.

HEART IMAGING Examples of kymogram-based reconstructions are given in Figs. 6, 7, and 8. The images clearly indicate the high quality of kymogram-based reconstruction. The patient shown in Fig. 8 is an example for an ECG-based reconstruction that failed. In this case, the ECG monitor reported twice as many R peaks as a result of a misinterpretation of the T waves. The kymogramcorrelated reconstructions of this patient are therefore of higher quality than the ECG-correlated images. It must be pointed out that the kymogram phase and the ECG phase are correlated up to an unknown scan- and patient-spe-

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Fig. 3. The detected center of mass (COM) is a function of the z position (and thus of time). The plots show that the COM is dominated by global patient structures, and the heart motion cannot be readily deduced therefrom.

Fig. 4. Scatter plot showing the unbiased cardiac motion for a complete scan (about 30 s of cardiac motion). The dots are colored according to a simultaneously acquired electrocardiogram signal. Dots of similar hue are located close together.

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Fig. 5. The kymogram’s K peaks are highly correlated to the electrocardiogram’s R peaks. Correlation is less optimal at the start and end of the scan, i.e., above and below the heart, where hardly any cardiac motion can be detected.

Fig. 6. Patient example reconstructed with the standard reconstruction algorithm extended parallel backprojection (EPBP) Std and with the phase-correlated reconstruction algorithm EPBP cardio-interpolation (CI) at 0% and 50% of KK, respectively. Parameters: 12 × 0.75-mm collimation, 0.42 s per rotation, 3-mm table increment.

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Fig. 7. Volume rendering of a kymogram-based volume reconstruction. The coronary arteries are depicted at great length.

Fig. 8. Case where two R peaks per heart cycle were assumed by the electrocardiogram (ECG)-based reconstruction as a result of a misinterpretation of the ECG’s T waves. The heart rate reported by the ECG monitor was 130 bpm, but the true heart rate was 65 bpm, and was detected by the kymogram algorithm. The images are reconstructed at a fixed z position (dashed lines in the plots above) at increments of 20% of RR and KK, respectively. Only the kymogram-based reconstructions show temporal contiguity.

cific constant, the so-called phase lag: Reconstructions at 0% of KK therefore do not necessarily correspond to reconstructions at 0% of RR. In cases with defect ECG signals, the phase lag is no longer constant (see Fig. 8).

THORACIC IMAGING Imaging of pericardial lung areas usually suffers from motion artifacts and blurring as a result of cardiac motion. The use of phase-correlated reconstruction algorithms promises to

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Fig. 9. Improved lung imaging using kymogram-correlated reconstruction for scans of the thorax. The motion artifacts at the borders of the heart and the double contours in the lung vanish using the kymogram.

Fig. 10. Pericardial motion can be greatly reduced using kymogram-correlated reconstruction.

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Fig. 11. The kymogram detection algorithm and complete reconstruction pipelines are available for clinical use, e.g., on the PC-based VAMP syngo Explorer workstation (17).

improve the image quality in lung imaging. In general, no ECG is acquired for standard thorax scans, and the use of kymogrambased reconstruction approaches applied to lung images is the method of choice (15,16). Figures 9 and 10 demonstrate results obtained from two patients scanned with a 16 × 0.75-mm collimation, a rotation time of 0.5 s, and a table increment of 6 mm per rotation (pitch 0.5). The scan mode allows us to cover a scan range of 40 cm during a single breath- hold. The potential for motion artifact reduction in the lung region can be seen in the axial displays and in the multiplanar reformations (inserts in Fig. 9). Blurring and double contours are greatly reduced by the kymogram-based approach.

CONCLUSIONS Synchronization alternatives can be used for those imaging cases where applying the ECG leads is inconvenient, and they may further serve as a fallback solution in cases of corrupted ECG signals.

One particular alternative to ECG correlation is the kymogram algorithm (Fig. 11). It is based on a COM tracking of the cardiac motion. Kymogram-gated reconstruction has proven to be adequate to image the heart and adjacent lung areas with high quality. The results are comparable to those of ECG-based synchronization. Kymogram correlation also seems to be especially useful to improve thoracic imaging in general. Potentially, it may replace ECG-based approaches in general and thereby eliminate the need for ECG hardware and efforts by personnel to record high-quality ECG signals.

REFERENCES 1. Kachelriess M, Kalender WA. ECG-based phase-oriented reconstruction from subsecond spiral CT scans of the heart. Radiology 1997;205(P):215. 2. Kachelriess M, Kalender WA, Karakaya S, et al. Imaging of the heart by ECG-oriented reconstruction from subsecond spiral CT scans. In: Glazer G, Krestin G (eds), Advances in CT IV. Springer Verlag, New York: 1998;137–143.

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3. Kachelriess M, Kalender WA. Electrocardiogram-correlated image reconstruction from subsecond spiral CT scans of the heart. Med Phys 1998;25(12):2417–2431. 4. Kachelriess M, Ulzheimer S, Kalender WA. ECG-correlated imaging of the heart with subsecond multi-slice spiral CT. IEEE Transactions on Medical Imaging 2000;19(9):888–901. 5. Taguchi K, Anno H. High temporal resolution for multislice helical computed tomography. Med Phys 2000;27(5):861–872. 6. Flohr T, Ohnesorge B, Kopp AF, Becker C, Halliburton SS, Knez A. A reconstruction concept for ECG-gated multi-slice spiral CT of the heart with pulse-rate adaptive optimization of spatial and temporal resolution. Radiology 2000;217(P):438. 7. Kachelriess M, Fuchs T, Lapp R, Sennst D-A, Schaller S, Kalender WA. Image to volume weighting generalized ASSR for arbitrary pitch 3D and phase-correlated 4D spiral cone-beam CT reconstruction. Proceedings of the 2001 Int. Meeting on Fully 3D Image Reconstruction 2001;179–182. 8. Kachelriess M, Sennst D-A, Kalender WA. 4D phase-correlated spiral cardiac reconstruction using image to volume weighting generalized ASSR for a 16-slice cone-beam CT. Radiology 2001; 221(P):457. 9. Kachelriess M, Kalender WA. Extended parallel backprojection for cardiac cone-beam CT for up to 128 slices. Radiology 2002;225(P):310. 10. Sourbelle K, Kachelriess M, Kalender WA. Feldkamp-type reconstruction algorithm for spiral cone-beam (CB) computed tomography (CT). Radiology 2002;225(P):451.

11. Kachelriess M, Knaup M, Kalender WA. Extended parallel backprojection for standard 3D and phase-correlated 4D axial and spiral cone-beam CT with arbitrary pitch and 100% dose usage. Med Phys 2004;31(6), in press . 12. Kalender WA, Kachelriess M. Computertomograph mit objektbezogener Bewegungsartefaktreduktion und Extraktion der Objektbewegungsinformation (Kymogramm). European Patent Office (Patent pending). 1999. 13. Kachelriess M, Kalender WA. Kymogram-correlated image reconstruction from subsecond multi-slice spiral CT scans of the heart. Radiology 2000;217(P):439. 14. Kachelriess M, Sennst D-A, Maxlmoser W, Kalender WA. Kymogram detection and kymogram-correlated image reconstruction from sub-second spiral computed tomography scans of the heart. Med Phys 2002;29(7):1489–1503. 15. Kachelriess M, Sennst D-A, Kalender WA. Reconstruction of motion-free pericardial lung images from standard spiral CT scans using kymogram correlation. Radiology 2002;225(P):403. 16. Lell M, Dassel M, Kalender WA, Bautz WA, Kachelriess M. Improvement of image quality in thoracic CT comparing standard reconstruction with kymogram-based reconstruction. Radiology 2002;225(P):567. 17. Sennst D-A, Kachelriess M, Leidecker C, Schmidt B, Watzke O, Kalender WA. Syngo explorer: an extensible software-based platform for reconstruction and evaluation fo CT images. RadioGraphics 2004;24:601–612.

CHAPTER 6 / RADIATION DOSE FROM CT

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Radiation Dose From CT of the Heart CYNTHIA H. MCCOLLOUGH, PhD

INTRODUCTION

To represent dose for a specific scan protocol, which almost always involves a series of scans, it is essential to take into account any gaps or overlaps between the radiation dose profiles from consecutive rotations of the X-ray source. This is accomplished with use of a dose descriptor know as the Volume CTDIw (CTDIvol), where

The issue of radiation dose from X-ray computed tomography (CT) has received much attention recently in both the popular media and scientific literature (1–5). This is in part due to the fact that the dose levels from CT typically exceed those from conventional radiography and fluoroscopy, and that the use of CT continues to grow. Thus, CT contributes a significant portion of the total collective dose from ionizing radiation delivered to the public from medical procedures. It is important, therefore, that physicians ordering or performing these examinations have an understanding of the dose delivered from a cardiac CT, as well as how that amount of radiation compares to those from other imaging procedures that use ionizing radiation.

CTDIvol = [(N × T)/ I ] × CTDIw and N = the number of simultaneous axial scans per X-ray source rotation T = the thickness of one axial scan (mm) I = the table increment per axial scan (mm) (10).

In helical CT, the ratio of the table travel per rotation (I) to the total nominal beam width (N × T) is referred to as pitch (10–11). Hence

HOW TO DESCRIBE THE DOSE FROM A CT EXAMINATION: CTDI AND DLP CT dose descriptors, the basic tools required for understanding radiation dose in CT, have been in existence for many years, yet continue to be refined as multidetector-row CT (MDCT) evolves. The primary measured value is known as the CT Dose Index (CTDI) and represents the integrated dose, along the z axis, from one axial CT scan (one rotation of the X-ray tube) (6–8) (Fig. 1). Typically, a 100-mm long ionization chamber is used for routine measurements. Thus, the subscript 100 is used to denote the measurement length. All other CT dose descriptors are derived from this primary measured value. It is important to note that the CTDI is always measured in the axial scan mode, and that doses for helical scan modes are calculated from the axial information. The equipment used to measure CTDI is shown in Fig. 2. The CTDI varies across the field of view. For example, for body CT imaging, the CTDI is typically a factor or two higher at the surface than at the center of the field of view. The average CTDI across the field of view is given by the weighted CTDI (CTDIw), where CTDIw = 2/3 CTDI(edge) + 1/3 CTDI(center) (9–10). Figure 3 gives the typical relative distribution of dose in the head and body phantoms. CTDIw is a useful indicator of scanner radiation output for a specific kVp and mAs. CTDIw is reported in terms of absorbed dose to air (9–10).

CTDIvol = (1/pitch) × CTDIw. So, whereas CTDIw represents the average radiation dose over the x and y directions, CTDIvol represents the average radiation dose over the x, y, and z directions. This provides a single CT dose parameter, based on a directly and easily measured quantity, which represents the average dose within the scan volume for a standardized (CTDI) phantom (10). CTDIvol is a useful indicator of the dose for a specific exam protocol, because it takes into account protocol-specific information such as pitch. Its value may be displayed prospectively on the console of newer CT scanners, although it may be mislabeled on some systems as CTDIw. Recent consensus agreement on these definitions is reflected in newer scanner software releases (10). Thus, CTDIvol estimates the average radiation dose within the irradiated volume of a CT acquisition. The SI units are milliGray (mGy). It does not indicate, however, the total energy deposited into the scan volume. Its value remains unchanged whether there are 20 or 40 scans acquired. To better represent the overall energy (or dose) delivered by a given scan protocol, the dose can be integrated along the scan length to compute the dose-length product (DLP), where DLP (mGy-cm) = CTDIvol (mGy) × scan length (cm) (9). The DLP reflects the total energy absorbed (and thus the potential biological effect) attributable to the complete scan acquisition. Thus, a limited abdomen CT might have the same

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Fig. 1. Computed Tomography Dose Index (CTDI) is the integral under the radiation dose profile from a single axial scan.

Fig. 2. Typical equipment used for measuring CT dose index.

Fig. 3. Typical dose distributions (%) across the image field-of-view.

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Table 1 Sample Volume CT Dose Index (CTDIvol) and Dose Length Product (DLP) Values for Common CT Exams

Peak kilovotage (kVp) Tube current (mA) Exposure time (s) Detector configuration (N × T) Table index per rotation (I) Pitch (I/N × T) Reconstructed scan width (mm) Scan length (cm) CTDIvol (mGy) DLP (mGy × cm)

Chest

Abdomen

120 200 0.5 4 × 5 mm 15 mm 0.75 5 40 12.0 480

120 300 0.5 4 × 5 mm 15 mm 0.75 5 20 19.1 382

Abdomen and pelvis 120 300 0.5 4 × 5 mm 15 mm 0.75 5 40 19.1 764

Table 2 Scan Acquisition Parameters, Volume CT Dose Index (CTDIvol), and Dose Length Product (DLP) for Coronary Calcification Imaging (12-cm scan length)

Data acquisition method Peak kilovotage (kVp) Tube current (mA)a Exposure time (s) Detector configuration (N × T) Table index per rotation (I) Pitch (I/N × T) Reconstructed scan width (mm) CTDIvol (mGy) DLP (mGy × cm) Effective doseb (mSv)

EBCT

MDCT1

MDCT1

MDCT2

MDCT2

Prospective triggering 130 630 0.1 1 × 3 mm 3 mm 1 3 3.5 42 0.7

Prospective triggering 120 140 0.36 4 × 2.5 mm 10 mm 1 2.5 4.6 55 0.9

Retrospective gating 120 100 0.5 4 × 2.5 mm 3.75 mm 0.375 3 12.5 150 2.6

Prospective triggering 120 150 0.33 4 × 2.5 mm 10 mm 1 2.5 4.7 56 1.0

Retrospective gating 120 150 0.5 4 × 2.5 mm 3.75 mm 0.375 2.5 20.3 243 4.1

a mA can be increased in multidetector-row CT (MDCT) scanners for larger patients to avoid an increase in image noise. The mA values for MDCT 1 and MDCT 2 were provided by the respective manufacturers, and do not necessarily produce an identical level of image noise. b Effective Dose estimate, with k = 0.017 mSv × (mGy × cm)–1. This value is averaged between male and female models (see text and ref. 5). EBCT, electron beam CT.

CTDIvol as an abdomen and pelvis CT, but the latter exam would have a greater DLP, proportional to the greater z extent of the scan volume. Table 1 demonstrates the differences in CTDIvol and DLP for typical body CT exams. The values are for demonstration only; they can vary by scanner model, vendor, and image quality requirements. Note that a change in technique (mAs/rotation) affects the CTDIvol, while a change in acquisition length (at the same technique) is reflected by the DLP. In cardiac CT, the anatomic scan length is relatively constant (typically 12 cm); thus, the variability in CTDIvol and DLP is primarily a result of differences in scanner output and scan acquisition parameters. Tables 2 and 3 provide the scan acquisition parameters, CTDIvol, and DLP for coronary calcification imaging and coronary angiography. Data are provided for an electron beam CT (EBCT) system as well as for MDCT systems from two different manufacturers.

AUTOMATIC EXPOSURE CONTROL It is technologically feasible for CT systems to adjust the X-ray tube current (mA) in response to variations in X-ray intensity at the detector (12–13), much as fluoroscopic X-ray systems adjust exposure automatically. This capability, in various implementations, is now available commercially on MDCT systems in response to wide interest from the radiology community. Some systems adapt the tube current based on changes in attenuation along the z axis, others adapt to changes in attenuation as the X-ray tube travels around the patient. The ideal is to combine both approaches with an algorithm that “chooses” the correct tube current to achieve a predetermined level of image noise. With regard to cardiac CT, the radiation dose for a retrospectively gated exam, where the X-ray tube is kept continuously on throughout the acquisition, can be dramatically reduced if the tube current is reduced during portions of the cardiac cycle

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Table 3 Scan Acquisition Parameters, Volume CT Dose Index (CTDIvol) and Dose Length Product (DLP) for Coronary Angiography (12-cm Scan Length)

Data acquisition method Peak kilovotage (kVp) Tube current (mA)a Exposure time (s) Detector configuration (N × T) Table index per rotation (I) Pitch (I/N × T) Reconstructed scan width (mm) CTDIvol (mGy) DLP (mGy × cm) Effective doseb (mSv)

EBCT

MDCT1

MDCT2

Prospective triggering 130 630 0.1 1 × 3 mm 2 mm 0.66 3 5.3 64 1.1

Retrospective gating 120 300 0.5 4 × 1 mm 1.5 mm 0.375 1.25 46 547 9.3

Retrospective gating 120 300 0.5 4 × 1.25 mm 1.9 mm 0.375 1.25 55 662 11.3

a mA can be increased in multidetector-row CT (MDCT) scanners for larger patients to avoid an increase in image noise. The mA values for MDCT 1 and MDCT 2 were provided by the respective manufacturers, and do not necessarily produce an identical level of image noise. b Effective Dose estimate, with k = 0.017 mSv × (mGy × cm)–1. This value is averaged between male and female models (see text and ref. 5). EBCT, electron beam CT.

that are not likely to be of interest for the reconstructed data. Thus, in addition to modulation of the tube current based on patient attenuation, the tube current can be modulated by the ECG signal. Since cardiac motion is least during diastole and greatest during systole, the projection data are least likely to be corrupted by motion artifact for diastolic-phase reconstructions. Accordingly, the tube current is reduced during systole. Dose reductions of approx 50% have been reported using such a strategy (14). The implementation of these and other dosereduction strategies is expected industry-wide over the next several years, in response to the strong concern about the radiation dose from CT.

EFFECTIVE DOSE It is important to recognize that the potential biological effects from ionizing radiation depend not only on the radiation dose, but also on the biological sensitivity of the tissue or organ system irradiated. A 100-mGy dose to an extremity would not have the same potential biological effect (detriment) as a 100-mGy dose to the pelvis (15). Effective dose (E) is a dose descriptor that reflects this difference in biologic sensitivity (16–17). It is a single dose parameter that reflects the risk of a nonuniform exposure in terms of an equivalent whole-body exposure. The units of E are milliSieverts (mSv). Although the concept of effective dose has some limitations when applied to medical populations, it does facilitate the comparison of biological effect between diagnostic exams of different types (16,17). Published values of E per DLP (9) allow convenient estimates of E based on the DLP value provided at the CT scanner console. The use of E facilitates communication with patients regarding the potential harm of a medical exam that uses ionizing radiation. For example, when a patient inquires, “What dose will I receive from this exam,” an answer in the units of mGy or mGy × cm will not likely answer the more

fundamental, but perhaps unspoken, question, “What is the likelihood that I will be harmed from this exam.” Characterizing the radiation dose in terms of E and comparing that value to some meaningful level—for instance, one year’s E from naturally occurring background radiation—better conveys to the patient the relative potential for harm from the medical exam. Table 4 provides typical values of E for several common imaging exams, as well as the annual level of background radiation in the US (approx 3.6 mSv). It is important to remember, however, that E describes the relative whole-body dose for a particular exam and scanner, but is not the dose for any one individual, as E calculations use many assumptions including a mathematical model of a “standard” human body that does not accurately reflect any one individual. Effective dose is best used to optimize exams and compare risks between proposed exams. It is a broad measure of risk, and as such should not be quoted with more than one or two significant digits. Specific values of E can be calculated using several different software packages (17), which are based on the use of data from one of two sources: the National Radiological Protection Board (NRPB) in the UK (18) or the Institute of Radiation Protection (GSF) in Germany (19). To minimize controversy over differences in E values that are purely the result of calculation methodology and data sources, a generic estimation method was proposed by the European Working Group for Guidelines on Quality Criteria in CT (9), where E is estimated from the noncontroversial value of DLP: E = k × DLP, where the values of k are dependent only on the region of the body being scanned (head, neck, thorax, abdomen, or pelvis) (Table 5). The values of E predicted by DLP and the values of E estimated using more rigorous calculation methods are remarkably consistent, with a maximum deviation from the mean of approx 10–15%. Hence, the use of DLP to estimate E appears to be a reasonably robust

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Table 4 Effective Dose Values for Common Imaging Examinations Examination

Effective dose (mSv)

Head CT Chest CT Abdomen and pelvis CT Selective coronary angiogram Posterior-anterior and lateral chest X-ray Average annual background radiation in the US

1–2 5–7 8–11 3–5 0.04–0.06 3.6

Table 5 Values of the Conversion Coefficient k for Use in Estimating Effective Dose (E) (mSv) From Dose Length Product (DLP) (in mGy × cm) According to the Formula E = k × DLP (9) Anatomic region

k (mSv × mGy–1 × cm–1)

Head Neck Chest Abdomen Pelvis

0.0023 0.0054 0.017 0.015 0.019

more publications regarding the clinical efficacy of cardiac CT as compared to alternate imaging modalities. Discussions of patient safety and societal cost will include discussions of the radiation dose from the various procedures. To ensure that these discussions are accurate, it is essential that the dose information associated with specific techniques be reported in an accurate and complete fashion using standardized terminology.

REFERENCES method for estimating E. The effective doses for several cardiac CT examinations, based upon values of DLP, are given in Tables 2 and 3.

SUMMARY The fundamental dose parameter in CT, the CTDI, is measured at edge and center locations in an acrylic phantom for a given kVp, mAs, and scan width, and reported for a given exam protocol as the volume CTDI (CTDIvol) in units of mGy. This value represents the average dose in a standard acrylic phantom for a given exam protocol. Another relevant dose parameter is that of effective dose, which is given in units of mSv. The effective dose is a single dose parameter that best represents the radiation detriment corresponding to a given exam protocol. Neither of these parameters is an estimate of radiation dose to any one individual, but rather should be used to optimize and compare exam protocols. E can be estimated with good accuracy from the DLP, which is equal to the CTDIvol multiplied by the total scan length (in cm). Techniques to modulate the tube current as a function of patient attenuation or the time within the cardiac cycle are important innovations that will reduce the dose from cardiac CT by at about a factor of two. Hence, coronary artery calcium examinations, which currently have E values between 1 and 4 mSv, may be able to be conducted using retrospective gating techniques and an E of less than 2 mSv. CT coronary angiography, which currently requires an E of approx 10 mSv with retrospectively gated MDCT may be performed with approx 5 mSv if ECG tube current modulation is applied. These effective dose values are of similar magnitude to those from a chest CT examination (5–7 mSv) or a conventional (diagnostic) coronary angiogram (3–5 mSv). Finally, as cardiac CT image quality, diagnostic accuracy, and availability all continue to improve, there will be more and

1. Brenner DJ, Elliston CD, Hall EJ, Berdon WE. Estimated risks of radiation-induced fatal cancer from pediatric CT. AJR 2001;176: 289–296. 2. Donnelly LF, Emery KH, Brody AS, et al. Minimizing radiation dose for pediatric body applications of single-detector helical CT: strategies at a large children’s hospital. AJR 2001;176:303–306. 3. Haaga JR. Radiation dose management. AJR 2001;177:289–291. 4. Nickoloff EL, Alderson PO. Radiation exposure to patients from CT: reality, public perception, and policy. AJR 2001;177:285–287. 5. Pierce DA, Preston DL. Radiation-related cancer risks at low dose among atomic bomb survivors. Radiation Research 2000;154:178–186. 6. Shope TB, Gagne RM, Johnson GC. A method for describing the doses delivered by transmission x-ray computed tomography. Med Phys 1981;8:488–495. 7. American Association of Physicists in Medicine. Standardized methods for measuring diagnostic x-ray exposures. Report no. 31. AAPM, New York, 1990. 8. Nagel HD. Radiation exposure in computed tomography. Frankfurt: COCIR, 2000. 9. European guidelines for quality criteria for computed tomography. Luxembourg: European Commission, 2000. 10. International Electrotechnical Commission. Medical Electrical Equipment. Part 2–44: Particular Requirements for the Safety of X-ray Equipment for Computed Tomography. IEC publication No. 60601-2-44 Amendment 1. 11. McCollough CH, Zink FE. Performance evaluation of a multi-slice CT system. Medical Physics 1999;26:2223–2230. 12. Gies M, Kalender WA, Wolf H, Suess C, Madsen M. Dose reduction in CT by anatomically adapted tube current modulation I: simulation studies. Medical Physics 1999;26:2235–2247. 13. Kalender WA, Wolf H, Suess C. Dose reduction in CT by anatomically adapted tube current modulation II: phantom measurements. Medical Physics 1999;26:2248–2253. 14. Jakobs TF, Becker CR, Ohnesorge B, et al. Eur Rad 2002;12: 1081–1086. 15. Committee on the Biological Effects of Ionizing Radiation. Health effects of exposure to low levels of ionizing radiation, BEIR V. Washington, DC: National Academy, 1990. 16. International Commission on Radiological Protection (ICRP). 1990 Recommendations of the ICRP. Publication 60. ICRP, New York, NY, 1991.

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17. McCollough CH, Schueler BA. Calculation of effective dose. Medical Physics 2000;27:828–837. 18. Jones DG, Shrimpton PC. Survey of CT practice in the UK. Part 3: Normalised organ doses calculated using Monte Carlo techniques, NRPB-250. Oxon, United Kingdom: National Radiological Protection Board, 1991.

19. Zankl M, Panzer W, Drexler G. The calculation of dose from external photon exposures using reference human phantoms and Monte Carlo methods. Part IV: Organ dose from computed tomographic examinations, GSF-Bericht 30/91. Neuherberg, Germany: GSF – Forschungszentrum fur Umwelt und Gesundtheit, Institut fur Strahlenschutz, 1991.

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DETECTION AND QUANTIFICATION III OF CORONARY CALCIUM

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Coronary Calcium Screening An Epidemiologic Perspective CHRISTOPHER J. O’DONNELL, MD, MPH AND UDO HOFFMANN, MD

INTRODUCTION

dynamics of coronary calcification under drug treatment. In this chapter, we review the strengths and limitations of available original research and discuss consensus statements of the American College of Cardiology/American Heart Association (ACC/AHA) regarding the use of CAC as an adjunct to established risk factors. We also provide insight into ongoing research and propose studies that could help to facilitate evidence-based practice guidelines.

Because coronary artery disease (CAD) is the most frequent cause of death in industrialized nations (1) and the available tools for prediction of CAD onset are imperfect, there is a need for new methods to screen apparently healthy individuals to identify those at increased risk. Current risk prediction of CAD is based on the patient’s age and sex as well as on the presence and extent of established, modifiable coronary risk factors such as hypertension, hyperlipidemia, diabetes mellitus, and cigarette smoking. Risk prediction algorithms such as the Framingham Heart Study coronary risk score have been shown feasible and valid for CAD risk prediction in the United States population (2). As a consequence, those traditional risk factors and/or risk-factor algorithms have been incorporated into treatment guidelines for hyperlipidemia (3) and hypertension.(4). However, coronary risk scores can explain only 70% of the overall risk for CAD and are more sensitive than specific. Consequently, there is need to develop new strategies to identify patients at high risk, specifically among patients who appear to be at intermediate (i.e., 6–20% 10-yr risk) or low risk according to traditional risk factors (5,6). Recently developed fast computed tomography (CT) techniques such as multidetector-row CT (MDCT) and electron beam CT (EBCT) now offer the opportunity to noninvasively detect and quantify coronary artery plaque burden (Figs. 1–4). The conduct of both techniques and their similarities and differences are described in detail elsewhere in this book. These CT scanners are capable of nearly freezing the motion of the heart as a result of very fast image acquisition and synchronization to ECG signals. Both have been shown to be highly sensitive for the detection of calcified coronary atherosclerotic plaques. A typical report from either MDCT or EBCT contains the Agatston score, a semiquantitative measure that is based on the area and a weighted density factor for coronary calcium. In the past decade, a large number of studies have been conducted to examine the predictive value of CT coronary artery calcium (CAC) as a predictor for coronary risk. In addition, this technique has been shown to be capable of following the natural history of coronary atherosclerosis and tracking the

CORONARY CALCIFICATION AND CORONARY ARTERY DISEASE Experts agree that CT testing can determine whether calcifications are present in the walls of the coronary arteries. If calcification of any amount is present, it follows that atherosclerosis is present in the coronary artery. Hence, patients with no symptoms but with detectable calcification can be said to have coronary artery disease not detectable by the usual clinical tests (“subclinical atherosclerosis”). However, there is controversy regarding the relation of the calcification score to the prevalence of CAD and the incidence of cardiac events such as unstable angina, myocardial infarction, and sudden cardiac death. Early studies by Rumberger (6a) showed that there is a linear relationship between the amount of calcium and the overall amount of atherosclerotic plaque. Logically, a number of studies have shown that high Agatston scores are associated with the presence and number of obstructive coronary artery lesions. While the technique appears to be quite sensitive, there is no one-to-one correlation, and the location of calcification and stenosis may be different. Two meta-analyses evaluated the diagnostic accuracy of CAC (EBCT) for the detection of significant coronary artery stenosis as compared to coronary angiography. In both studies, the overall sensitivity and specificity of CAC were 80–90% and 40–50%, with a maximum joint value of 75%, respectively (7,8). Moreover, the summary odds ratios were increased 20-fold (95% confidence interval [CI], 5 to 88) indicating that the odds of having a significant coronary artery stenosis are 20 times higher if calcium was detected. However, the generalizability of these studies is limited—most of the patients were middle-aged men. Apart from a small number of studies where most patients were referred to angiography as a result of chest pain, the indication for coronary angiography was not specified. However, most likely almost all patients were symptomatic for CAD or had known

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Fig. 1. A cross-sectional image through the aorta and the origin of the left coronary artery (dashed arrow). A moderate amount of calcification can be easily identified as bright signals (solid arrows).

Fig. 2. A cross-sectional image through the aorta; a moderate amount of calcification can be easily identified as bright signals (arrows).

Fig. 3. A cross-sectional image through the aorta (Ao), the left ventricle (LV) and the right atrium (RA). Left image: high image quality, no image artifacts, aortic valve calcification. Right image: image artifacts in the right coronary artery (solid arrow) and mitral valve calcification (dashed arrow).

CAD. Consequently, the prevalence of disease (CAD) was very high in the study populations (with one exception >50%, in about a third of the studies 70–95%), and the clinically important question “What is the probability of having/not having significant CAD given a positive/negative test?” (positive pre-

dictive value/negative predictive value) is difficult to answer. In addition, most studies were designed only as observational studies, and blinding was not mentioned as a quality criterion in all but two of the analyzed studies. In summary, the available information is still limited, and the results cannot be general-

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Fig. 4. A cross-sectional image through the aorta and the left atrium. Left image: high image quality, no image artifacts, arrow pointing at the circumflex and the left coronary artery. Right image: image artifacts in the circumflex, the left coronary artery, and the aortic valve (arrows).

ized. As a consequence, the use of CAC for the accurate prediction of prevalent significant CAD has not been implemented into clinical guidelines.

PREDICTIVE VALUE OF CORONARY CALCIFICATION FOR CARDIOVASCULAR EVENTS Clinicians are currently interested in the role of CAC in prediction of cardiovascular events. Since a large proportion of all cardiovascular events occur in asymptomatic patients, it is justified to differentiate asymptomatic persons from symptomatic patients with known CAD.

CORONARY CALCIFICATION IN ASYMPTOMATIC PERSONS A small number of prospective studies have evaluated the prediction of cardiac events by coronary calcification. In a recent meta-analysis of prospective studies, there was an increased risk for a combined outcome (nonfatal myocardial infarction [MI], congenital heart disease [CHD], death, or revascularization) associated with a calcium score elevated above a median value (risk ratio 8.7 [95% CI, 2.7–28.1]). The relative risk of hard endpoints (MI or death) was also increased (risk ratio 4.2 [95% CI 1.6–11.3]) (9). Three more recent prospective studies have added data from more than 20,000 patients to the meta-analysis. In 5635 asymptomatic, low-tomedium-risk men and women self-referred for EBCT, there were 224 events, of which only 61 were “hard” endpoints (MI

or death) after 37 ± 12 mo of follow-up. After adjustment for risk factors ascertained by questionnaire, there were statistically increased risks associated with the presence of CAC for hard events in men (95% CI, 3.9 [1.2–13]) and no significantly increased risks in women (95% CI, 1.5 [0.2–10]) (10). In a second prospective study of all-cause mortality in 10,377 selfreferred men and women, there were 249 deaths in approx 60 mo of follow-up. Increasing CAC scores were associated with significantly increased relative risks for death, and receiver operating characteristics (ROC) curves were significantly greater for CAC score added to risk factors compared with risk factors alone (p < 0.001) (11). In a third prospective study of 5585 men and women recruits in whom an EBCT test was obtained to decide upon eligibility for inclusion in a randomized controlled lipid lowering trial, there were 122 events, of which 43 were hard events after over 50 mo of follow-up. Overall, there were statistically increased risks for hard events (9.9 [5.2–18.9]) as well as all endpoints associated with a high CAC score. In an analysis of the incremental predictive ability of CAC over Framingham risk score in a subset of 1817 subjects in whom risk factors was measured, there was a severalfold increase in risk for cardiovascular endpoints in the highest compared with the lowest tertile of CAC score (12).

LIMITATIONS OF THE AVAILABLE DATA While there is consistency across the available studies for an association of CAC scores with the presence of significant CAD

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and the risk of cardiovascular events, a number of methodological concerns make it difficult to interpret study results and apply them to clinical practice. Importantly, there are concerns regarding study generalizability/external validity, validity of the risk factor measures, and resultant multivariable models used in the studies. In addition, the conclusions are drawn from relatively small numbers of hard cardiovascular outcomes (all together numbering only several hundred). A major limiting factor of most studies has been the inclusion of self-referred patients. None of the available evidence for CAC screening has been drawn from community-based cohorts representative of typical populations which might be considered for screening. Subjects studied to date have a high prevalence of subclinical CAD and CAD risk factors, often making them different from persons in the community of a similar age and sex. The baseline characteristics of many of these cohorts suggest that patient populations already at substantially elevated risk have been studied. Thus, data from these studies may not be representative of apparently healthy lowand medium-risk groups for whom screening may be more relevant. Moreover, the self-referred subjects to date may differ significantly in other unmeasured characteristics that accompany health-seeking behaviors. In the available studies, data are limited for young persons, women, and non-Caucasians. Much of the data to date have been derived largely from middle-aged Caucasian men. As a consequence of this selection bias, age- and gender-specific CAC thresholds for younger individuals for subjects below 40 yr of age, women, and non-Caucasian populations may be relatively unreliable due to lack of statistical power (small sample sizes, insufficient numbers of events) or wholly unavailable. Potentially important racial differences in prevalence of CAC have been noted in the Multiethnic Study of Atherosclerosis (MESA) (13); in particular, the prevalence of CAC appears to be lower in African Americans and other major ethnic groups in the United States (14–16). Another significant concern pertains to the method of ascertainment of risk factor data. It has been suggested that a high CAC score predicts coronary risk independently and probably incrementally to traditional coronary risk factors and coronary risk scores. ROC curve analyses are often provided to bolster the case for CAC screening over and above risk factors. However, in virtually every available study, blood pressure determinations, lipid levels, and other risk factors are obtained retrospectively by questionnaire, self-report from the study patient, and/or review of the medical record. There is a substantial risk of misclassification in self-reported risk-factor data. Therefore, calculations of Framingham coronary risk or other multivariable risk models using self-reported risk factors algorithms would tend to underestimate the risk conferred by risk factors (bias towards the null) and lead to a more favorable comparison of CAC scores with risk factors. Standardized research methods that mirror office-based methods for measurement of blood pressure, lipid levels, and diabetes have not been employed in the available studies. By way of contrast, prospective epidemiologic cohort studies such as the Framingham Heart Study and the Multiethnic Study of Athero-

sclerosis are recording risk factor data prospectively. A final set of concerns pertains to study follow-up and outcomes. First, the level of completion of follow-up is inconsistent across studies, with some studies having less than 90% follow-up. For example, in one of the largest recent studies, only a 64% follow-up was achieved (10). Losses to follow-up can raise questions about the validity of study findings. A second concern is the focus of the available studies on either combined hard (i.e., MI and death) and/or soft (i.e., revascularization using percutaneous coronary interventions or coronary artery bypass surgery) outcomes. Soft intervention outcomes are often used, but may not be appropriate because neither the study patients nor their physicians were blinded to the CAC score. Thus, given the fact that many patients were self-referred and not part of a blinded study, there is a substantial risk that soft outcomes may be contaminated by intervention bias introduced by knowledge of the CAC test results. No study with cardiovascular mortality as a primary outcome has been reported to date, and in virtually all available studies, there have been too few cardiovascular deaths to reliably examine the association of CAC. The recent study of Shaw et al. shares many of the limitations of the other self-referral studies, but it did report a positive association of CAC score with all-cause mortality (11). One strength of the Shaw study was its demonstration of consistent, statistically significant increases in mortality across increasing CAC scores in a large cohort. Nevertheless, mortality data were drawn from the National Death Index, and no further data on cause of death or on non-fatal outcomes were ascertained (11). Interestingly, there is a small and growing body of evidence in population-based cohorts that calcification of the aorta predicts risk for CAD and other cardiovascular diseases independent of measured risk factors. The prevalence of calcified lesions detected on thoracic and abdominal radiographs like that of coronary calcium, increases steeply with age (17). A number of recent studies have demonstrated that thoracic and abdominal aortic calcifications are independent, prospective predictors of CVD. Calcification of the aortic arch detected by plain antero-posterior radiographs predicts an increased risk of cardiovascular diseases in men and women (18). In the Framingham Heart Study, the presence and extent of abdominal aortic calcification detected by lateral lumbar radiographs is a predictor of CVD, CVD mortality, and CHD in middleaged men and women (mean age 60 yr), independent of age and actually measured cardiovascular risk factors (17). Abdominal aortic calcification would likely be detected quite reliably and accurately by CT imaging, and further study of the prognostic value of such CT findings in addition to or instead of coronary calcium is clearly warranted.

ADDITIONAL QUESTIONS SURROUNDING CAC SCREENING A number of additional concerns have arisen surrounding CAC screening and are summarized in Table 1. First, the CT test does lead to significant exposure to radiation. The test exposes the patient to a limited amount of ionizing radiation (0.7 to 3 mSv) that is equivalent to 25–100% of the natural background radiation exposure that an individual in the United

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Table 1 Suggested Guidelines and Implications for Coronary Artery Calcium Scoring (Adapted From Partner’s HealthCare System 2002 Guidelines) Guidelines for ordering a CT test for coronary calcium Coronary calcium screening is not recommended for asymptomatic individuals at low risk. Coronary calcium screening will be performed only upon a physician’s request. Patients should be informed that most insurers do not reimburse for coronary screening. The out-of-pocket expense for a multidetector-row CT test for coronary calcium is $350–$450. A positive calcium score might be valuable in determining whether a patient who appears to be at intermediate congenital heard disease (CHD) risk is actually at high risk. However, we do not currently recommend coronary calcium scoring for this group. Ongoing research will better define the clinical subgroups, such as elderly asymptomatic persons or those with a strong family history, in whom the management of other risk factors might be modified according to the calcium score. Guidelines for Interpreting a CT Test for Coronary Calcium Some patients and physicians will choose to obtain coronary calcium studies despite the lack of consensus for these studies. We recognize that clinicians who might not have ordered the test themselves are increasingly faced with the test “results” and asked for their advice. Therefore the following comments are provided from the recent ACC/AHA consensus document: In the absence of coronary calcium (i.e., a “negative” CT test) Atherosclerotic plaque, including unstable plaque, is very unlikely, although it is possible that significant coronary atherosclerosis may not be detected. Significant luminal obstructive disease is highly unlikely. Angiographically normal coronary arteries occur in the majority of such patients. The absence of calcium may be consistent with a low risk of CHD events over the next 2 to 5 yr. For a test that is positive for coronary calcium: The presence of calcium confirms the presence of a coronary atherosclerotic plaque. The greater the amount of calcium, the greater the likelihood of occlusive coronary artery disease, although there is not a one-to-one relationship, and findings may not be site specific. The total amount of calcium correlates best with the total amount of atherosclerotic plaque, although the true “plaque burden” is underestimated. A high calcium score (e.g., Agatston score > 400) may be consistent with moderate–high risk of CHD events over the next 2–5 yr.

Fig. 5. 90th Percentile Agatston scores derived from large numbers of men and women screened with electron beam CT. Data from ref. 22.

States receives per year (2.5 to 3 mSv). This is less than the dose received during a diagnostic cardiac catheterization (approx 4.5 mSv) and only a fraction of the occupational exposure limit for a radiation worker in the United States (50 mSv/y). Although the available data suggest that these risks are extremely low from such exposure (19), for some individuals even this low risk may be considered unacceptably high. Second, several recent studies have demonstrated that there is a high prevalence of potentially clinically important findings that are incidentally detected on CT scans (20,21). Such incidental findings may provoke significant anxiety in the patient and may require

additional exposure to radiation or even invasive testing in order to confirm or exclude a potentially serious diagnosis such as an aortic aneurysm or malignancy. Third, as mentioned above, unbiased data on age-adjusted coronary calcium thresholds are not yet available, because the available data are derived from cohorts that may or may not be representative of general screening subjects. Moreover, simple thresholds (such as an Agatston score of 400) that do not adjust for age may overestimate risk in older persons and underestimate risk in younger persons (Fig. 5) (22). A fourth and related concern is the fact that many different CT scan machines are now available (including both

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EBCT and MDCT machines) and standardized scanning and scoring algorithms have not been implemented across machine types. Moreover, there is a small but significant level of measurement variability consistently seen across all scanner types, and the degree of variability may differ. Fifth, all CAC scoring to date has been conducted using the Agatston score. While the Agatston score has provided an invaluable reference score for research to date, newer mass-based scoring techniques may substantially reduced the misclassification introduced by image noise. A final concern regarding CT scanning is its currently high cost. The cost for the test ranges from $375–$450, and the test is not currently covered by most health insurance providers.

nations of lipid-lowering agents, anti-platelet therapies, and angiotensin-converting enzyme inhibitors. While the optimal indications for the use of noninvasive tests for clinical monitoring of the response to therapy remain to be determined, existing expert consensus statements such as that provided by the ACC/AHA in 2000 provide cogent standards for the present time. CAC testing has not yet been reliably shown to add incremental information for risk stratification in generalizable patient cohorts, and ongoing studies should address the important outstanding questions regarding the appropriate types of men and women in whom to consider coronary calcium screening.

CRITICAL EVIDENCE NEEDED FOR CLINICAL GUIDELINES

REFERENCES

Both risks and benefits must be considered for any potential screening test. The benefits would include potential for reduction of risk provided by an accurate diagnosis of increased risk and the potential benefits from early detection of incidental findings (e.g., small lung cancers). The risks include the morbidity and mortality risk of an incorrect diagnosis (negative or positive), risks of radiation exposure, morbidity and mortality from detection of benign incidental findings, and high costs of potentially unnecessary testing. The current body of studies suggests that there may be a role for CAC screening, but to date there are no strong unbiased data for or against CAC screening over and above traditional risk-factor assessments in the general population. The limitations of existing studies can be addressed only by prospective, observational studies conducted in unbiased, population-based cohorts of both Caucasian and nonCaucasian men and women. It has been suggested that coronary calcium screening may be most beneficial in persons at intermediate coronary risk (5,6). At least 40% of the population of middle-aged men and women may fall into this category (5). In the proposed studies, risk-factor measurements should be office-based rather than self-reported. Ideally, measures of risk factors as well as coronary calcification would be conducted in as blinded a manner as possible. Several such population-based studies are currently underway. These studies include the Framingham Heart Study and the Multiethnic Study of Atherosclerosis. Final recommendations regarding use of CT calcium awaits the completion of these studies.

CONCLUSION Coronary atherosclerosis underlies CHD and is influenced by the interaction of multiple risk factors over time in a susceptible host. Traditional risk-prediction models, such as the Framingham risk score, are reasonable predictors of CHD risk. Interest in CAC screening is aimed at improving the prediction of risk for future clinical events. Future studies will need to ascertain the incremental benefit of CAC measures over traditional risk factors and the cost effectiveness of incorporating such measures into global risk-assessment algorithms. In the future, CAC tests may play an important role in assessment of patients at intermediate risk for CHD events. Higher-risk individuals may be candidates for more aggressive pharmacological risk-factor modification using combi-

1. American Heart Association. 2000 Heart and Stroke Statistical Update. 2000. Dallas, Texas, American Heart Association. 2. Wilson PW, D’Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation 1998;97: 1837–1847. 3. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143–3421. 4. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560–2572. 5. Greenland P, Smith JS, Jr., Grundy SM. Improving coronary heart disease risk assessment in asymptomatic people: role of traditional risk factors and noninvasive cardiovascular tests. Circulation 2001;104:1863–1867. 6. Wilson PW, Smith SC, Blumenthal RS, et al. Task force #4—how do we select patients for atherosclerosis imaging? J Am Coll Cardiol 2003;41:1898–1906. 6a. Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz RS. Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study. Circulation 1995;92:2157–2162. 7. Nallamothu BK, Saint S, Bielak LF, et al. Electron-beam computed tomography in the diagnosis of coronary artery disease: a metaanalysis. Arch Intern Med 2001;161:833–838. 8. O’Rourke RA, Brundage BH, Froelicher VF, et al. American College of Cardiology/American Heart Association expert consensus document on electron-beam computed tomography for the diagnosis and prognosis of coronary artery disease. J Am Coll Cardiol 2000;36: 326–340. 9. O’Malley PG, Taylor AJ, Jackson JL, et al. Prognostic value of coronary electron-beam computed tomography for coronary heart disease events in asymptomatic populations. Am J Cardiol 2000;85: 945–948. 10. Kondos GT, Hoff JA, Serukov A, et al. Electron-beam tomography coronary artery calcium and cardiac events: a 37-month follow-up of 5635 initially asymptomatic low- to intermediate-risk adults. Circulation 2003;107:2571–2576. 11. Shaw LJ, Raggi P, Schisterman E, Berman DS, Callister TQ. Prognostic value of cadiac risk factors and coronary artery calcium screening for all-cause mortality. Radiology 2003;228:826–833. 12. Arad Y, Roth M, Newstein D, Guerci AD. Coronary calcification, coronary disease risk factors, and atherosclerotic cardiovascular disease events: the St. Francis Heart Study. J Am Coll Cardiol Abstract 2003. 13. Bild DE, Bluemke DA, Burke GL, et al. Multi-ethnic study of atherosclerosis: objectives and design. Am J Epidemiol 2002; 156:871–881. 14. Hatwalkar A, Agrawal N, Reiss DS, et al. Comparison of prevalence and severity of coronary calcium determined by electron beam

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15. 16.

17.

18.

tomography among various ethnic groups. Am J Cardiol 2003; 91:1225–1227. Budoff MJ, Yang TP, Shavelle RM, et al. Ethnic differences in coronary atherosclerosis. J Am Coll Cardiol 2002;39:408–412. Lee TC, O’Malley PG, Feuerstein I, et al. The prevalence and severity of coronary artery calcification on coronary artery computed tomography in black and white subjects. J Am Coll Cardiol 2003; 41:39–44. Wilson PW, Kauppila LI, O’Donnell CJ, et al. Lumbar aortic calcification is an important predictor of vascular morbidity and mortality. Circulation 2001;103:1529–1534. Witteman JC, Kannel WB, Wolf PA, et al. Aortic calcified plaques and cardiovascular disease (the Framingham Study). Am J Cardiol 1990;66(15):1060–1064.

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19. Morin RL, Gerber TC, McCollough CH. Radiation dose in computed tomography of the heart. Circulation 2003;107:917–922. 20. Horton KM, Post WS, Blumenthal RS, et al. Prevalence of significant noncardiac findings on electron-beam computed tomography coronary artery calcium screening examinations. Circulation 2002;106:532–534. 21. Hunold P, Schmermund A, Seibel RM, et al. Prevalence and clinical significance of accidental findings in electron-beam tomographic scans for coronary artery calcification. Eur Heart J 2001;22: 1748–1758. 22. Hoff JA, Chomka EV, Krainik AJ, Daviglus M, Rich S, Kondos GT. Age and gender distributions of coronary artery calcium detected by electron beam tomography in 35,246 adults. Am J Cardiol 2001;87(12):1335–1339.

CHAPTER 8 / CORONARY CALCIUM SCANNING: WHY

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Coronary Calcium Scanning Why We Should Perform It AXEL SCHMERMUND, MD, STEFAN MÖHLENKAMP, MD, AND RAIMUND ERBEL, MD

It is increasingly recognized that only by preventing ischemic heart disease can morbidity and mortality associated with cardiovascular diseases be substantially reduced. There are two main preventive strategies: one that focuses on community-wide measures (“population approach”) and one that focuses on high-risk individuals (“high-risk approach”) (1). Certainly, both approaches have strengths and limitations, and should work best if applied in a complementary fashion. Although clear goals can be set for community-wide measures (such as promoting healthy diet, increasing physical activity, and marginalizing smoking), strategies for successful implementation depend on political, cultural, and economic surroundings. Trials in Central and Western Europe have failed to fulfil the expectations (2,3). By contrast, the high-risk approach has been demonstrated to be effective regarding both lifestyle and pharmacological interventions (1). The problem with this approach is the need to reliably identify high-risk subjects. Risk prediction algorithms derived from large epidemiological studies—in particular the Framingham study and the Münster (Germany) Procam study (4,5)—serve as the cornerstone of office-based risk assessment. Absolute 10-yr risk of myocardial infarction or cardiac death is calculated. However, risk factors identify adverse outcomes in a population. Because of the wide variability of atherosclerosis in subjects with formally identical risk-factor exposure (6), individual discrimination is often unsatisfactory (7). Further, there is considerable uncertainty as to the application in external populations with different characteristics (8–11). The Framingham algorithm appears to overestimate absolute risk in a German population by approx 50% (11). To estimate the risk of a coronary event, risk-factor assessment is the most common procedure, and this is justified by overwhelming evidence. Risk factors lead to events by the patho-physiological intermediary of atherosclerotic plaque disease. In this sense, risk factors yield a statistical probability that coronary plaques have developed. Coronary calcium scanning allows for direct visualization of coronary atherosclerotic plaque disease. It can answer the question of whether risk-

factor exposure in the actual individual has really led to the development of coronary atherosclerosis. The cumulative effect of risk-factor exposure over many years can be assessed by its impact on coronary plaque development (12). There is a relationship between the extent of calcified plaque burden and that of total plaque burden (13,14). Thus, the primary aim is not to diagnose coronary stenoses, but rather to detect and quantify coronary plaque burden. Importantly, coronary calcium in many instances seems to indicate coronary disease activity. Calcium is a frequent feature of plaque rupture (found in 70–80% of cases) (15–17). Among all types of plaques that can be defined histologically, the extent of calcium is greatest in healed plaque rupture, which is frequently observed in sudden coronary death (16,18). Further, calcium is associated with positive arterial remodeling (19). The mechanisms leading to positive arterial remodeling appear to share common aspects with those ultimately leading to plaque rupture, and plaques displaying positive remodeling of the arterial segment are prone to rupture. All prospective studies in seemingly healthy older adults have found substantial increases in relative risk of a cardiovascular hard event in the presence of increased amounts of coronary calcium (20–25). Consistently, a very high negative predictive value (99%) regarding cardiovascular hard endpoints has been reported. Conversely, high-risk persons were identified whose risk exceeded an event rate of 2% per year (20–25). These studies have prompted the authors of the American Heart Association Prevention Conference V and the National Cholesterol Education Program Adult Treatment Panel III to list electron beam computed tomography coronary calcium scanning as a possible diagnostic modality in adults with several risk factors, in particular older adults (26,27). The actual guidelines for the prevention of CAD issued by the European Society of Cardiology and other leading European societies (European Heart Journal) expand on this. It is stated that the calcium score “is an important parameter to detect asymptomatic individuals at high risk for future CVD events, independent of the traditional risk factors” (28). The favorable data from the above-mentioned trials were all obtained in selected cohorts, which has been criticized. Recently, however, results from population-based studies with unselected participants have confirmed these results. The

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Fig. 1. Sixty-one-year-old male who agreed to participate in the Heinz Nixdorf Recall Study, an epidemiological project in the general population, 3 d after having run the Cologne marathon in 4:28 h. The man was in very good health and feeling well. His only cardiovascular risk factor was systemic hypertension, yielding a Framingham risk of 12% (intermediate risk category) and a Procam risk of 5.7% (low risk category). The electrocardiograph recording in the setting of the Heinz Nixdorf Recall Study and further laboratory analyses revealed subacute anterior myocardial infarction. The left panel shows his electrocardiogram with T inversion in I, aVL and V4-V6 (arrows) and slow R progression. His total coronary calcium score determined by electron-beam CT was 1105 (right panel). The figure shows a section at the base of the heart with massive calcification of the left main stem and proximal portion of the left anterior descending coronary artery. He had more coronary calcium than approx 94% of males his age (94th percentile). Coronary angiography showed severe three-vessel disease with left main stem involvement. He underwent successful aorto-coronary bypass surgery with complete revascularization and had an uneventful course.

SCHMERMUND, MÖHLENKAMP, AND ERBEL

CHAPTER 8 / CORONARY CALCIUM SCANNING: WHY

Rotterdam Coronary Calcification Study and the St. Francis Heart Study, with a total of almost 7600 healthy subjects, have consistently observed relative risks associated with elevated coronary calcium scores on the order of 8–11 (29–31). In both population-based studies, the predictive power of coronary calcium was independent of and additive to risk-factor information. In the Rotterdam study, subjects with a Framingham risk score below the median who had a calcium score in the upper tertile had a relative risk of 8.9 compared with subjects with the same Framingham risk score whose calcium score was in the lower tertile (30). Imaging of coronary calcium allows direct detection of coronary atherosclerotic plaques and estimation of the extent of disease and its distribution in the coronary tree (32). As opposed to other methods of direct vessel wall diagnostics such as B-mode ultrasound analysis of carotid artery intima-media thickness and plaques, coronary atherosclerosis can be directly assessed. As opposed to noninvasive exercise tests such as exercise stress testing or stress echocardiography, actual coronary plaques are detected, with all the consequences regarding comparative predictive abilities. Coronary calcium scanning adds previously unachievable prognostic power to the information derived from risk-factor analysis. An example is shown in Fig. 1. Coronary calcium scanning is helpful in particular in healthy subjects with an undetermined cardiovascular risk whose management is unclear. In these subjects, the coronary calcium score can direct the treating physician towards general advice in the case of a low or negative score, or towards intensive treatment in the case of a high score. If the score is intermediate, this is also helpful. The physician has much more security that indeed, an intermediate risk is present and the patient can be treated accordingly. Finally, selected symptomatic patients with known coronary artery disease can benefit from coronary calcium scanning if detailed information on the extent of atherosclerotic plaque disease is needed and prognostication is especially important.

REFERENCES 1. Yusuf S, Reddy S, Ôunpuu S, Anand S. Global burden of cardiovascular disease. Part II: variations in cardiovascular disease by specific ethnic groups and geographic regions and prevention strategies. Circulation 2001;104:2855–2864. 2. World Health Organization European Collaborative Group. European Collaborative Trial of Multifactorial Prevention of Coronary Heart Disease. Final report on the 6-year results. Lancet 1986;1: 869–872. 3. Thelle D. Prevention of cardiovascular diseases: a scientific dilemma. Scand Cardiovasc J 2000;34:103–105. 4. Wilson PWF, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation 1998;97:1837–1847. 5. Assmann G, Cullen P, Schulte H. Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the prospective cardiovascular Munster (PROCAM) study [erratum: Circulation 2002;105:900]. Circulation. 2002;105: 310–315. 6. Greenland P, Abrams J, Aurigemma GP, et al. Prevention Conference V. Beyond secondary prevention: identifying the high-risk patient for primary prevention. Noninvasive tests of atherosclerotic burden. Writing Group III. Circulation 2000;101:e16–e22.

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7. Wald NJ, Law M, Watt HC, et al. Apolipoproteins and ischaemic heart disease: implications for screening. Lancet 1994;343:75–79. 8. D’Agostino RB Sr, Grundy S, Sullivan LM, Wilson P. CHD Risk Prediction Group. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. JAMA 2001;286:180–187. 9. Laurier D, Chau NP, Cazelles B, Segond P. PCV METRA Group. Estimation of CHD risk in a French working population using a modified Framingham model. J Clin Epidemiol 1994;47:1353–1364. 10. Menotti A, Puddu PE, Lanti M. Comparison of the Framingham risk function-based coronary chart with risk function from an Italian population study. Eur Heart J 2000;21:365–370. 11. Hense HW, Schulte H, Lowel H, Assmann G, Keil U. Framingham risk function overestimates risk of coronary heart disease in men and women from Germany—results from the MONICA Augsburg and the PROCAM cohorts. Eur Heart J 2003;24:937–945. 12. Hoeg JM, Feuerstein IM, Tucker EE. Detection and quantitation of calcific atherosclerosis by ultrafast computed tomography in children and young adults with homozygous familial hypercholesterolemia. Arterioscler Thromb 1994;14:1066–1074. 13. Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz RS. Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study. Circulation 1995;92:2157–2162. 14. Schmermund A, Denktas AE, Rumberger JA, et al. Independent and incremental value of coronary artery calcium for predicting the extent of angiographic coronary artery disease: comparison with cardiac risk factors and radionuclide perfusion imaging. J Am Coll Cardiol 1999;34:777–786. 15. Farb A, Burke AP, Tang AL, et al. Coronary plaque erosion without rupture into a lipid core. A frequent cause of coronary thrombosis in sudden coronary death. Circulation 1996;93:1354–1364. 16. Burke AP, Taylor A, Farb A, Malcom GT, Virmani R. Coronary calcification: insights from sudden coronary death victims. Z Kardiol 2000;89 Suppl 2:49–53. 17. Schmermund A, Erbel R. Current perspective: unstable coronary plaque and its relation to coronary calcium. Circulation 2001; 104: 1682–1687. 18. Burke AP, Kolodgie FD, Farb A, et al. Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression. Circulation 2001;103:934–940. 19. Burke AP, Kolodgie FD, Farb A, et al. Morphological predictors of arterial remodeling in coronary atherosclerosis. Circulation 2002; 105:297–303. 20. Raggi P, Callister TQ, Cooil B, et al. Identification of patients at increased risk of first unheralded acute myocardial infarction by electron-beam computed tomography. Circulation 2000;101:850–855. 21. Arad Y, Spadaro LA, Goodman K, Newstein D, Guerci AD. Prediction of coronary events with electron beam computed tomography. J Am Coll Cardiol 2000;36:1253–1260. 22. Wong ND, Hsu JC, Detrano RC, Diamond G, Eisenberg H, Gardin JM. Coronary artery calcium evaluation by electron beam computed tomography and its relation to new cardiovascular events. Am J Cardiol 2000;86:495–498. 23. Park R, Detrano R, Xiang M, et al. Combined use of computed tomography coronary calcium scores and C-reactive protein levels in predicting cardiovascular events in nondiabetic individuals. Circulation 2002;106:2073–2077. 24. Kondos GT, Hoff JA, Sevrukov A, et al. Electron-beam tomography coronary artery calcium and cardiac events: a 37-month follow-up of 5635 initially asymptomatic low- to intermediate-risk adults. Circulation 2003;107:2571–2576. 25. Shaw LJ, Raggi P, Schisterman E, Berman DS, Callister TQ. Prognostic value of cardiac risk factors and coronary artery calcium screening for all-cause mortality. Radiology 2003;228:826–833. 26. Greenland P, Smith SC, Grundy SN. Current perspective: improving coronary heart disease risk assessment in asymptomatic people. Role of traditional risk factors and noninvasive cardiovascular tests. Circulation 2001;104:1863–1867.

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27. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. Circulation 2002;106:3143–3421. 28. De Backer G, Ambrosioni E, Borch-Johnsen K, et al. Executive Summary. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J 2003;24:1601–1610. 29. Vliegenthart R, Oei HH, Breteler MM, et al. Coronary calcification is a strong predictor of all-cause and cardiovascular mortality in elderly. Circulation 2002;106(Suppl):II–743.

30. Vliegenthart R. Coronary calcification and the risk of cardiovascular disease. An epidemiologic study. PhD Thesis. Thoraxcentre Rotterdam, Netherlands, March 19, 2003. 31. Arad Y, Roth M, Newstein D, Guerci A. Coronary calcification, coronary disease risk factors, and atherosclerotic cardiovascular disease events: the St. Francis Heart Study. Hotline Session, ACC 2003. 32. Schmermund A, Baumgart D, Möhlenkamp S, et al. Natural history and topographic pattern of progression of coronary calcification in symptomatic patients: an electron-beam CT study. Arterioscler Thromb Vasc Biol 2001;21:421–426.

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Detection and Quantification of Coronary Calcium With Electron Beam CT AXEL SCHMERMUND, MD, STEFAN MÖHLENKAMP, MD, AND RAIMUND ERBEL, MD

TECHNIQUE

this scoring algorithm, it should not be completely abandoned in favor of more recent algorithms.

Electron beam computed tomography (EBCT) employs well-known computed tomography technology. However, in distinction to other CT machines, no mechanical parts are moved. Whereas in usual CT machines, the distance between cathode and anode is very short, it measures approx 9 ft in EBCT. The electron beam, which produces the X-rays by striking the anode, is steered over this distance by an electromagnetic deflection system. The latest generation of EBCT machines (e-Speed™, GE Imatron) achieves an image acquisition time of only 30 ms, which is sufficient to freeze the motion of the heart. Standardized methods for imaging, identification, and quantification of coronary calcium using EBCT have been established (1,2). The current generation of EBCT scanners is usually operated in the high-resolution mode with continuous, nonoverlapping slices of 3-mm thickness and an acquisition time of 100 ms. Patients are positioned supine, and a sufficient number of slices is obtained to cover the complete heart through the apex (usually 36–40 slices). Electrocardiographic triggering is performed at a fixed point within the RR interval, generally 40% or 80%. Coronary calcium is defined as a hyperattenuating lesion above the threshold of a CT density of 130 Hounsfield units (HU) in an area of two or more adjacent pixels. The calcium score is a product of the area of calcium and a factor rated 1–4, dictated by the maximum CT density (1). The calcium score can be calculated for a given coronary segment, a specific coronary artery, or for the entire coronary system (Fig. 1). More recently, a volumetric score has been introduced, which uses isotropic interpolation and may thus be more reproducible (3). Further, calcium mass measurements have been suggested, which would render measurements obtained with various CT technologies (EBCT or spiral CT with different slice thickness) comparable (4). Such measurements require simultaneous phantom calibration and are currently not widely available. Because the above-mentioned calcium score has been employed since 1990, and all long-term data are based on

CORONARY CALCIUM—WHAT DOES IT MEAN? Non-contrast-enhanced cardiac EBCT allows for direct, noninvasive visualization of calcified coronary plaques (Fig. 1). The primary aim is not to diagnose coronary stenoses, but rather to detect and quantify coronary plaque burden. Coronary plaques, usually not highly stenotic, are the underlying substrate of the acute coronary syndromes (5). Coronary calcium is a specific expression of coronary atherosclerotic plaque disease (6,7). There is a relationship between the extent of calcified plaque burden and that of total plaque burden (6–9). Total plaque burden is one of the most important predictors of coronary risk (10,11). The more calcium detected, the more plaque there is. This carries direct implications for an individual’s coronary risk (5). It may be argued that calcium is associated with an overall increased activity of coronary atherosclerotic disease. Histopathologic studies have demonstrated that coronary calcium is a frequent feature of plaque rupture (5,12,13) and is found even in subjects who die of sudden coronary death as the first manifestation of ischemic heart disease under the age of 50 yr (14). Among all types of histologically defined types of plaques detected in young victims of sudden coronary death, acute ruptures contain calcium most frequently (80%), while healed ruptures contain the greatest amount of calcium (13,15). Plaque erosions, on the other hand, are associated with little calcium (12,13). Calcium is found preferentially in plaques with expansive (“positive”) arterial remodeling (16). The mechanisms leading to expansive arterial remodeling appear to share common aspects with those ultimately leading to plaque rupture, and plaques displaying positive remodeling of the arterial segment are prone to rupture (17). Finally, lesions characterized by ultrasound radiofrequency analysis as unstable frequently contain calcium (18). The findings in studies using conventional intravascular ultrasound have been less unequivocal, perhaps as a result of differences in the ability to define calcium and lesion characteristics (19–23). Whereas some studies have detected less calcium in the culprit lesion in patients with unstable angina

From: Contemporary Cardiology: CT of the Heart: Principles and Applications Edited by: U. Joseph Schoepf © Humana Press, Inc., Totowa, NJ

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Fig. 1. Coronary calcium scans at the level of the left anterior descending coronary artery. Left panel: No coronary calcium. Mid panel: Moderate coronary calcium with typical localization in the area of bifurcation with first diagonal branch, total calcium score 108. Right panel: Extensive coronary calcium, total calcium score 3.532.

pectoris or acute myocardial infarction than in patients with stable symptoms (19–21), others did not find a difference (22,23), or, in a prospective study, detected more calcium in patients who later sustained an event (24). In summary, coronary calcium indicates the presence and extent of coronary atherosclerotic plaque disease. The weight of evidence suggests that coronary calcium indicates atherosclerotic disease activity and is associated with healed or acute plaque rupture and positive arterial remodeling.

CORONARY CALCIUM—WHAT DOES IT PREDICT? In patients presenting to the emergency room with chest pain and no initial objective signs of myocardial ischemia, a negative EBCT indicated an excellent prognosis with regard to major cardiac events over the subsequent 1–4 mo (25–27). EBCT yielded negative predictive values in the range of 98–100%. In symptomatic patients undergoing coronary angiography, increased amounts of coronary calcium detected by EBCT were highly predictive of subsequent events over 30 mo (28–30). In direct comparison, EBCT performed better than coronary angiography (that is, number of stenotic major coronary arteries) in this respect (28–30). A number of studies have examined the predictive value of EBCT coronary calcium quantification in selected asymptomatic populations. All of these studies have demonstrated that the coronary calcium score predicts coronary events, defined as an aggregate of coronary death, nonfatal myocardial infarction, and revascularization (Table 1). Arad et al. observed that the prespecified calcium score cutpoints of 80 and 160 both were associated with odds ratios of approx 22 for suffering coronary death or acute myocardial infarction, with wide confidence intervals (CIs) (95% CI, 5.1–97.4 and 6.4–77.4, respectively) (31). There was a tendency for higher scores in subjects with hard events compared to subjects who underwent revascularization. In this study, the status of established risk factors was

determined by questionnaire. In a multivariate analysis in a subgroup of patients with all information available (n = 787), the calcium score cutpoints were associated with odds ratios for suffering any event in the range of 14–20 and the risk factors, including age, with odds ratios in the range of 3–6 (31). Raggi et al. found that subjects with calcium scores in the highest quartile had an odds ratio of 21.5 (95% CI, 2.8–162.4) for suffering acute myocardial infarction or cardiac death (32). Risk factor data were obtained by questionnaire. Subjects in the highest quartile of cardiovascular risk factor distribution had an odds ratio of 7.0 (95% CI, 1.6–31.5). Wong et al. assessed risk factors (by questionnaire) and coronary calcium scores in 881 subjects. After adjustment for risk factors, coronary calcium scores in the third or fourth quartile were associated with a relative risk of 4.5 or 8.8 (33). Accordingly, these three studies suggest that EBCT was independent of risk-factor information for predicting events and was clearly superior compared with risk-factor analysis alone. However, risk factors were determined only by questionnaire. Detrano et al. reported an odds ratio of 2.7 associated with a calcium score above the median (34). Receiver operating curve analysis of calcium scores for separating subjects with vs without acute myocardial infarction or coronary death yielded an area under curve (± SE) of 0.64 ± 0.05. For comparison, this value was 0.86 ± 0.07 in the study by Arad et al. (31). Risk factors were assessed by questionnaire and direct measurements of laboratory values. An ECG was recorded in all subjects. The combined analysis of risk factors and ECG yielded an area under the curve of 0.69 ± 0.05, so that for predicting hard events, EBCT was not superior in this report. However, in a later analysis of the same data set, but excluding diabetic subjects, coronary calcium was a strong and independent predictor of coronary death and nonfatal myocardial infarction as well as revascularization (35). After adjustment for risk factors, the relative risk of sustaining a hard event was 4.9–6.1

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Table 1 Prognostic Studies in Selected Patient Populations

No. of events (%)

Patients with event: calcium score (mean ± SD, median)

Patients without event: calcium score (mean ± SD, median)

Author (reference)

No. of patients

Mean age

Women (%)

Mean calcium score

Median calcium score

Follow-up (mo)

Arad (31)

1177

53 ± 11

29

~ 156

4

43

39 (3.3)

764 ± 935 (511)

135 ± 432 (3)

14.3

Raggi (32)

632

52 ± 9

50

101 ± 254

3.1

32

27 (4.3)

303 ± 441 (141)

92 ± 240 (2.4)

12.5

Wong (33)

926

54 ± 10

21

143

5

40

28 (3.0)

n/a

n/a

4.5a

Detrano (34)

1196

66 ± 8

11

452 ± 457

44

41

46 (3.8)

n/a

n/a

2.3

Park (35)

967

66 ± 8

10

n/a

n/a

77

104

395 ± 571 (203)

195 ± 378 (37)

4.4– 7.5a

aAdjusted

RR

Definition of events Coronary death, nonfatal MI, revasc. Coronary death, nonfatal MI MI, revasc., cerebrovasc. event Coronary death, nonfatal MI, revasc. Coronary death, nonfatal MI, revasc.

for risk factors. SD, standard deviation; MI, myocardial infarction.

in the highest vs the lowest tertile of calcium scores (depending on the level of C-reactive protein), and the risk for all endpoints (including revascularization) was 4.4–7.5. In this analysis, coronary calcium was superior to combined risk-factor analysis (on the basis of actual laboratory data) and ECG and also to C-reacting protein (35). These findings were corroborated by the analysis of large databases with a total of >15,000 patients (36,37). Kondos et al. examined subjects who were all self-referred and who were followed over a mean of 3.1 yr. They observed a relative risk of myocardial infarction or cardiac death of 7.2 in men with a coronary calcium score in the upper quartile (36). In women, the event rate was only 0.4%, so that no meaningful analysis was possible. Shaw et al. documented only total mortality (37). A calcium score in the range between 400 and 1000 was associated with a 6.2-fold increase in death rate. A calcium score >1000 was associated with a 12.3-fold increase in death rate. Perhaps the most important aspect of these studies was that high-risk persons could be identified whose risk exceeded a rate of 2% per year (hard events) (36,37) or 1% per year for overall mortality. Along the same lines, Wahys et al. reported retrospective data (38). In analogy with a study in symptomatic patients (30), asymptomatic patients with very high calcium scores (>1000) had a greatly elevated risk of sustaining an event (38). The Rotterdam Coronary Calcification Study was the first population-based study to have yielded data in unselected participants (39,40). In this project, 2013 persons from a suburb of Rotterdam, the Netherlands, were recruited. After a mean follow-up time of 2.7 yr, 116 cardiovascular events occurred, in-

Fig. 2. Rate of coronary artery disease (CAD)-related deaths associated with different coronary calcium scores in the Rotterdam Coronary Calcification Study, a population-based study. Mean follow-up was 2.7 yr (38).

cluding 73 coronary heart disease deaths. There was a strong and graded relationship between the EBCT-derived calcium score and cardiovascular disease events (39). The 15% of participants with the highest scores had a relative risk of 11 of dying from ischemic heart disease. The yearly death rate regarding only ischemic heart disease was almost 2% (Fig. 2). In the approx 50% of participants with low or negative calcium scores, this rate was only 0.07% (39). After adjustment for risk factors, the association between coronary calcium scores and cardiovascular as well as coronary morbidity and mortality

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Table 2 Indications for the Use of CT Coronary Calcium Scanning Asymptomatic persons: 1. Persons with risk factors who cannot be determined by office-based risk assessment to have either a low or a high cardiovascular risk 2. Older persons in whom the established risk factors lose some of their predictive value and whose risk remains indeterminate Symptomatic persons: 3. Patients in whom advanced risk stratification is useful, for example if extensive coronary plaque disease is suspected 4. Patients presenting to the emergency room with nonspecific chest pain (“rule out myocardial infarction”)

remained strong (40). The relative risk of coronary heart disease increased gradually in patients with higher coronary calcium scores compared with those in the reference category with calcium scores of 0–100, which comprised 50% of all participants (40). It was 3.2 in subjects with scores of 101–500, 5.1 in subjects with 501–1000, and 8.3 in subjects with scores >1000. The coronary event rates in 2.7 yr were 0.8% in the lowest score group and increased to 3.3%, 5.0%, and 8.7% in the other calcium score groups. In summary, the EBCT-derived coronary calcium score has demonstrated its ability to identify subjects with a very low risk of cardiovascular and coronary disease as well as subjects with a very high rate of events (>2% per year). This ability goes beyond that of conventional risk-factor analysis, is independent of it, and adds incremental predictive value.

PROGRESSION OF CORONARY CALCIUM Follow-up coronary calcium scans appear to be useful, as the progression of calcification is influenced by low-density lipoprotein values and can be attenuated or even stopped by lipid-lowering (“statin”) medication (3,41). In patients followed in an outpatient setting, the progression of coronary calcium burden is approx 25% per year (42). However, there is great inter-individual variability, probably as a result of the interplay of numerous factors which influence the process. Also, baseline plaque burden determines the rate of progression (42). Progression is observed at typical predilection sites of atherosclerosis in the coronary tree. Changes in overall coronary calcium result from uniform changes at these sites. This uniform pattern of change suggests that the development of calcified plaque disease is a coronary systemic process (42). In patients with elevated cholesterol values, progression of coronary calcium appears to be accelerated and on the order of 50% per yr (3). In patients treated with statin therapy, the annual progression is substantially reduced. Values between 10 and 20% per year have been reported (3,41). If low-density lipoprotein (LDL)-cholesterol can be reduced to levels <100 mg/dL, it appears possible to stop the progression of coronary calcium (41). The value of coronary calcium scanning for assessing the treatment effect in individual patients remains to be clarified.

CORONARY CALCIUM—HOW CAN IT BE USED? There are four major areas where EBCT scanning for coronary calcium can offer clinical value (Table 2). 1. Application of coronary calcium scoring to define the extent of coronary atherosclerosis in asymptomatic individuals at risk for coronary disease is of great interest. The

magnitude of the problem warrants tools for improved risk prediction, and published data suggest a prominent role for EBCT. However, it is currently unresolved who benefits from an EBCT scan in terms of future coronary events which can be prevented on the basis of the calcium study. Clearly, the indications for a scan need to be strictly defined to avoid “overdiagnosis” and disproportionate increases in health care expenditure. Indeed, the authors of the American Heart Association Prevention Conference V and the National Cholesterol Education Program Adult Treatment Panel III list coronary calcium scanning as a useful diagnostic modality in adults with several risk factors, in particular older adults (43,44). Fig. 3 shows how coronary calcium scoring might be used to improve individual risk stratification. The most recent statement is provided in the actual guidelines for the prevention of CAD issued by the European Society of Cardiology and other leading European societies (45). The European guidelines state that the calcium score “is an important parameter to detect asymptomatic individuals at high risk for future CVD events, independent of the traditional risk factors.” This statement expands on the previous statements (43,44). The interpretation of the EBCT scan is straightforward with regard to prognostication, and it indeed applies to any person regardless of symptomatic status. Because it is internationally comparable, the Agatston calcium score remains the standard algorithm, but an increasing role of calcium area and/or volume-scoring algorithms can be expected. The absence of identifiable coronary calcium is consistent with no or at most minimal coronary atherosclerosis. Individuals in this group fall into a favorable prognostic group. On the other hand, Agatston calcium scores exceeding 80–100 are highly consistent with at least nonobstructive CAD (46,47). The presence of moderate calcium scores in an otherwise asymptomatic individual suggests that further evaluations may be prudent, including careful identification and aggressive treatment of modifiable risk factors. It cannot be overemphasized that calcium scores need to be interpreted with regard to age and sex distribution. According to the natural history of coronary atherosclerosis, calcium scores increase in higher age groups. At the same time, the prognostic significance is shifted, because clinically overt coronary artery disease occurs in some patients with increasing age, but not in others. With this in mind, individuals with significant coronary calcium (calcium score >400–500) clearly have advanced coronary atherosclerosis and require strict measures regarding modifiable risk factors. Additionally,

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Fig. 3. Algorithm for the use of electron beam CT coronary calcium scanning for advanced risk stratification (41,42). In patients in whom officebased risk assessment determines an intermediate risk level (approx 40% of patients), calcium scanning can be used for further—advanced— risk stratification (box). Even in the presence of a rather intermediate calcium score, the scan is useful. In this case, the probability of a truly intermediate risk is much greater than if determined by office-based risk assessment alone. Of note, the initial office-based risk estimate might be less accurate than the aggregate risk estimate including coronary calcium scanning. It is open to question whether one should concentrate on examining intermediate-risk patients in order to define their management more precisely or whether some patients with a presumably low or high risk on the basis of office-based risk assessment may also profit from undergoing a coronary calcium scan.

Fig. 4. Algorithm used by the authors for interpreting electron-beam computed tomography coronary calcium scans (2). In a first step, the total calcium score is considered. Because of the relationship between coronary calcified and coronary total plaque burden, a high calcium score indicates a high coronary plaque burden. In a second step, the total calcium score is put in perspective regarding age and sex of the individual person. If the calcium score is greater than expected (above the median value), cardiovascular risk is increasingly elevated.

depending on all available clinical information, further evaluations should probably be considered to determine the potential for myocardial ischemia (47). Apart from the calcium score, age and sex of the patient should be considered by using specific percentile values (“normogram”) such as those provided for >35,000 adults in ref. 48. These percentile values were calculated on the basis of EBCT studies. They appear to be very similar to values derived with four-slice spiral CT (49). But, dynamic changes in imaging parameters need to be considered that may pose problems regarding the comparability and appli-

cation of data from one system to another. On the basis of these considerations, the German Working Group on Cardio-CT has suggested a scheme for interpretation of EBCT coronary calcium scans (Fig. 4) (2). 2. The issues explained above also pertain to symptomatic patients with known coronary artery disease in that the extent of coronary arteriosclerosis represents an important predictor of events (28–30). Therefore, coronary calcium scanning may be helpful in selected individuals with coronary artery disease where it appears particularly important to obtain complete prognostic information.

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3. The absence of coronary calcium by EBCT has negative predictive values between 90% and 100% for obstructive CAD (25–27). This appears of value in the patient with no prior clinical coronary artery disease who presents to the emergency department with chest pain or a questionable ischemic syndrome, but a negative or nondiagnostic ECG and negative cardiac enzymes. Recent studies in this setting have demonstrated that the negative predictive value is 99–100% (25–27). Especially in a patient with a low to intermediate likelihood of obstructive coronary artery disease, a negative EBCT could thus facilitate early dismissal from the emergency department or chest pain unit. Conversely, if the calcium score is consistent with moderate or severe coronary atherosclerosis, then additional cardiac evaluation might be appropriate. Finally, in a patient with an indeterminate or otherwise questionable stress test result, EBCT can be valuable by adding anatomic information on the extent of coronary atherosclerosis to the information on the functional significance of the disease sought with the stress test. Otherwise, in this group of patients, the same issues apply as explained above. 4. The progression of coronary atherosclerosis is an important area of research and has considerable implications with regard to an adverse prognosis in the presence of accelerated disease progression. Recent investigations have documented substantial progress in the reliability of EBCT scanning (50,51). The median variability of an EBCT scan repeated in the same patient within a few minutes is much less than the annual rate of progression found in symptomatic or high-risk patients (3,41,42). Indeed, EBCT enables tracking the progression of calcified plaque disease, which appears to parallel the mode of progression in angiographic studies and predicts future myocardial infarction (52). Recent data suggest that the influence of risk-factor modification on disease progression can be evaluated non-invasively using EBCT. This offers a new avenue for following patients both with regard to the prognosis related to differential progression of coronary atherosclerosis and with regard to the effect of various treatment strategies. At present, the ability of EBCT to monitor the efficacy of therapeutic interventions appears established only for small groups of patients and not necessarily for individuals. There is substantial variability of progression in patients with apparently similar risk-factor profiles under treatment. However, this may only reflect the complex, multifactorial nature of the disease. The use of EBCT to assess therapeutic interventions by direct visualization of the coronary arteries holds great promise. Further, the first available data suggest that subjects with increased progression of coronary calcium are much more likely to sustain a clinical event than subjects with less progression (52,53).

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23. de Feyter PJ, Ozaki Y, Baptista J, et al. Ischemia-related lesion characteristics in patients with stable or unstable angina. A study with intracoronary angioscopy and ultrasound. Circulation 1995;92: 1408–1413. 24. Abizaid AS, Mintz GS, Abizaid A, et al. One-year follow-up after intravascular-ultrasound assessment of moderate left main coronary artery disease in patients with ambiguous angiograms. J Am Coll Cardiol 1999;34:707–715. 25. Laudon DA, Vukov LF, Breen JF, Rumberger JA, Wollan PC, Sheedy PF II. Use of electron-beam computed tomography in the evaluation of chest pain patients in the emergency department. Ann Emerg Med 1999;33:15–21. 26. McLaughlin VV, Balogh T, Rich S. Utility of electron beam computed tomography to stratify patients presenting to the emergency room with chest pain. Am J Cardiol 1999;84:327–328. 27. Georgiou D, Budoff MJ, Kaufer E, Kennedy JM, Lu B, Brundage BH. Screening patients with chest pain in the emergency department using electron beam tomography: a follow-up study. J Am Coll Cardiol 2001;38:105–110. 28. Detrano R, Hsiai T, Wang S, et al. Prognostic value of coronary calcification and angiographic stenoses in patients undergoing coronary angiography. J Am Coll Cardiol 1996;27:285–290. 29. Keelan PC, Bielak LF, Ashai K, et al. Long-term prognostic value of coronary calcification detected by EBCT in patients undergoing coronary angiography. Circulation 2001;104:412–417. 30. Möhlenkamp S, Lehman N, Schmermund A, Grönemeyer D, Seibel R, Erbel R. Electron beam CT-based coronary calcium quantities predict future hard events in symptomatic males with advanced coronary artery disease—a 5 year follow-up study. Eur Heart J 2003;92:845–854. 31. Arad Y, Spadaro LA, Goodman K, Newstein D, Guerci AD. Prediction of coronary events with electron beam computed tomography. J Am Coll Cardiol 2000;36:1253–1260. 32. Raggi P, Callister TQ, Cooil B, et al. Identification of patients at increased risk of first unheralded acute myocardial infarction by electron-beam computed tomography. Circulation 2000;101:850–855. 33. Wong ND, Hsu JC, Detrano RC, et al. Coronary artery calcium evaluation by EBCT and its relation to new cardiovascular events. Am J Cardiol 2000;86:495–498. 34. Detrano RC, Wong ND, Doherty TM, et al. Coronary calcium does not accurately predict near-term future coronary events in high-risk adults [published errata in Circulation 2000;101:697 and Circulation 2000;101:1355]. Circulation 1999;99:2633–2638. 35. Park R, Detrano R, Xiang M, et al. Combined use of computed tomography coronary calcium scores and C-reactive protein levels in predicting cardiovascular events in nondiabetic individuals. Circulation 2002;106:2073–2077. 36. Kondos GT, Hoff JA, Sevrukov A, et al. Electron-beam tomography coronary artery calcium and cardiac events: a 37-month follow-up of 5635 initially asymptomatic low- to intermediate-risk adults. Circulation 2003;107:2571–2576. 37. Shaw LJ, Raggi P, Schisterman E, Berman DS, Callister TQ. Prognostic value of cardiac risk factors and coronary artery calcium screening for all-cause mortality. Radiology 2003;228:826–833. 38. Wayhs R, Zelinger AB, Raggi P. High coronary artery calcium scores pose an extremely elevated risk for hard events. J Am Coll Cardiol 2002;9:225–230.

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39. Vliegenthart R, Oei HH, Breteler MM, et al. Coronary calcification is a strong predictor of all-cause and cardiovascular mortality in elderly. Am Heart Association Scientific Sessions 2002 (Abstract no. 3651). 40. Vliegenthart R. Coronary calcification and the risk of cardiovascular disease. An epidemiologic study. PhD Thesis. Thoraxcentre Rotterdam, Netherlands, March 19, 2003. 41. Achenbach S, Ropers D, Pohle K, et al. Influence of lipid-lowering therapy on the progression of coronary artery calcification: a prospective evaluation. Circulation 2002;106:1077–1082. 42. Schmermund A, Baumgart D, Möhlenkamp S, et al. Natural history and topographic pattern of progression of coronary calcification in symptomatic patients: an electron-beam CT study. Arterioscler Thromb Vasc Biol 2001;21:421–426. 43. Greenland P, Smith SC, Grundy SN. Current perspective: Improving coronary heart disease risk assessment in asymptomatic people. Role of traditional risk factors and noninvasive cardiovascular tests. Circulation 2001;104:1863–1867. 44. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. Circulation 2002;106:3143–3421. 45. De Backer G, Ambrosioni E, Borch-Johnsen K, et al. Executive Summary. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J 2003;24:1601–1610. 46. Rumberger JA, Sheedy PF, Breen JF, Schwartz RS. Electron beam computed tomographic calcium score cutpoints and severity of associated angiographic lumen stenosis. J Am Coll Cardiol 1997;29: 1542–1548. 47. Rumberger JA, Brundage BH, Rader DJ, Kondos G. Electron beam computed tomographic coronary calcium scanning: a review and guidelines for use in asymptomatic persons. Mayo Clin Proc 1999; 74:243–252. 48. Hoff JA, Chomka EV, Krainik AJ, et al. Age and gender distributions of coronary artery calcium detected by electron beam tomography in 35,246 adults. Am J Cardiol 2001;87:1335–1339. 49. Schmermund A, Erbel R, Silber S. Age and gender distribution of coronary artery calcium measured by four-slice computed tomography in 2,030 persons with no symptoms of coronary artery disease. Am J Cardiol 2002;90:168–173. 50. Adamzik M, Schmermund A, Reed JE, Adamzik S, Behrenbeck T, Sheedy PF 2nd. Comparison of two different software systems for electron-beam CT-derived quantification of coronary calcification. Invest Radiol 1999;34:767–773. 51. Achenbach S, Ropers D, Möhlenkamp S, et al. Variability of repeated coronary artery calcification measurements by electron beam tomography. Am J Cardiol 2001;87:210–213. 52. Raggi P, Cooil B, Shaw LJ, et al. Progression of coronary calcium on serial electron beam tomographic scanning is greater in patients with future myocardial infarction. Am J Cardiol 2003;92: 827–829. 53. Arad Y, Roth M, Newstein D, Guerci A. Coronary calcification, coronary disease risk factors, and atherosclerotic cardiovascular disease events: the St. Francis Heart Study. Hotline Session, ACC 2003.

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Detection and Quantification of Coronary Calcium With Dual-Slice CT JOSEPH SHEMESH, MD

INTRODUCTION

rarely contain a few calcium granules. Atheroma, type IV lesions, emerge primarily in the decade after puberty at the highly susceptible artery sites, and immediately contain calcium granules within some smooth muscle cells and extracellularly among the vast mass of lipidic particles (the lipid core) that now forms, replaces, and expands an extensive region in the deep intima. According to Stary (1), cell organelles were damaged and sequestered calcium. Intracellular calcium granules become extracellular when dead cells break up, but calcification of cell components apparently also occurs only after their release into the extracellular space after cell disintegration. Lipidic cell remnants can calcify, including matrix vesicles, cell membranes, secondary and tertiary lysosomes, macrophage foam cells, and smooth muscle cells. The atheromas of people up to early middle age do not often obstruct the arterial lumen much, but are vulnerable to rupture or fissuring, leading to acute coronary syndrome (2). These potentially dangerous lesions cannot be detected by the current noninvasive diagnostic methods, which are all based on flowlimiting protruding lesions that obstruct at least 50% of the vessel lumen. This preclinical stage of CAD can be detected by the high resolution of the spiral technique, providing a potential means for population screening and an anatomical basis for primary prevention measures. The proportion of lipid-to-calcium deposit is much higher in young than old people. From about the fifth decade of life, advanced lesions contain lumps and plates of calcium rather than, or in addition to, the much smaller granules. Granules increase in size by encrustation, and adjacent granules fuse to form the larger structures. Type V and VI lesions contain large-sized deposits but continue to have a core of extracellular lipid. In high-grade calcifications, designated as type VII lesions, mineral dominates over all other lesion components. Lamellar bone (osseous metaplasia) may be present in such lesions. Type V–VII lesions are more often associated with lumen obstruction, forming the basis of the chronic manifestations of CAD, stable angina pectoris (SAP) with generally ischemic changes upon stress tests diagnostic modalities. These symptomatic obstructive lesions require revascularization by angioplasty or bypass operation—the “chronic,” “soft,” or “interventional” events.

The introduction of dual-slice spiral technique by Elscint in 1992 allowed the imaging of the heart with 3-mm slices within 30 s (a breath-hold). The advantage of double-helical computed tomography (DHCT) over single-slice helical CT is its ability to acquire data twice as fast as single-slice helical CT owing to its two parallel arcs of detectors that are simultaneously irradiated by a single node. Both single- and dualslice techniques acquire a volume of spatial information over several seconds without electrocardiographic gating. These data can be reconstructed into thin overlapping axial images, with an acquisition time for each image of approx 0.6–1.0 s. The use of overlapping methods compensates for the absence of electrocardiogram (ECG) triggering, enabling the detection of minimal spotty calcific lesions with an area threshold of 0.5 mm2. This technique was further improved by the 4and 16-slice multidetector spiral techniques, which enable the use of ECG triggering with subsecond slice time. The dual-slice technique of the Twin system (Philips LTD) is a contribution to practical cardiology. The noninvasive detection and measurement of the early stages of atherosclerosis within the wall of the coronary arteries provides the clinician with a new perspective on coronary artery disease (CAD) and adds important information to the current noninvasive methods. This chapter will summarize our experience of using the coronary calcium score in clinical practice.

CORONARY CALCIUM AND ATHEROSCLEROSIS In order to recommend the most appropriate diagnostic test for each individual, it is essential to recognize the underlying process of the disease. For CAD, it is atherosclerosis, which starts early in life. Atherosclerotic lesions (types I and II) are found in 69% of children by the time of puberty (1). The changes are minimal in such lesions—lipids have not yet accumulated exracellularly, the matrix between cells remains unchanged, and they are not associated with the emergence of calcium deposits. Type III lesions are the link between the minimal changes of children and the atheroma of adults, and From: Contemporary Cardiology: CT of the Heart: Principles and Applications Edited by: U. Joseph Schoepf © Humana Press, Inc., Totowa, NJ

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Fig. 1. The main indications for coronary calcium screening are summarized in relation to stages of the atherosclerotic process. Screening: asymptomatic individuals may have mild to moderate amounts of coronary calcifications (CC) (Stary stages III–IV), or may have earlier noncalcific plaques (Stary I–II). At these stages the current noninvasive tests are normal, as well as the coronary angiogram. The goal of the coronary scan is to provide a more sensitive screening tool, in order to introduce early primary preventive measures to treat the atherosclerosis systematically. Diagnostic: the diagnosis of heavy calcifications (Stary V–VII) helps to confirm the presence of obstructive disease in clinically equivocal patients. The goal is to identify obstructive vessels for revascularization in order to treat ischemia and anginal symptoms. Coronary CT for this indication should not be confused with its use as a screening tool.

CLINICAL MANIFESTATION OF CAD: CHRONIC VS ACUTE CAD is clinically manifested by two different main syndromes. The acute syndrome strikes suddenly as sudden death, acute myocardial infarction (AMI), or unstable angina. This syndrome is related to fissure or rupture of one or more vulnerable plaques, generally characterized by a lipid-rich core and thin, fibrous cap. The chronic CAD syndrome manifests when obstructive lesions develop over many years, resulting in ischemic changes upon stress tests, with angina pectoris (AP), or without pain (silent ischemia) (Fig. 1). Pathologic, angiographic, and intracoronary ultrasound studies reveal sharp differences in the distribution of coronary atherosclerosis and plaque morphology between these two coronary syndromes. Utilizing DHCT, we evaluated the coronary calcium patterns in 149 patients: 47 with chronic SAP and 102 patients surviving a first AMI (3). Prevalence of coronary calcium was 81% among the AMI patients and 100% in the SAP patients. The 547 calcific lesions identified in the AMI patients and the 1242 lesions in the SAP patients were categorized into three groups according to their extent: mild, intermediate, and extensive. The age-adjusted percentages of the highest level of calcification, among AMI vs SAP patients, were as follows: mild 18 vs 3%, intermediate 49 vs 18%, and extensive lesions 33 vs 79% respectively (p < 0.01). In the AMI group, 73 culprit arteries were identified; 16 (22%) had no calcium detected, while 30 (41%) showed mild lesions, 20 (27%) had intermediate forms,

and only 7 (10%) had extensive lesions. We demonstrated in this study that extensive calcium characterizes the coronary arteries of patients with chronic SAP, whereas first AMI most frequently occurs in mildly calcified or noncalcified culprit arteries. We recently confirmed this observation in a prospective study (4), which investigated the underlying calcific atherosclerotic lesions in a cohort of 50 hypertensive patients who sustained acute vs chronic coronary events. Their mean age was 66 ± 6 yr, and 78% were male. They were all participants in the INSIGHT calcification study and sustained a coronary event during a 3-yr follow-up. Twenty-nine patients had an acute and 21 had a chronic event. High prevalence of coronary artery calcification (CAC) (total calcium score [TCS] >0) was observed in both groups: 93% in the acute and 96% in the chronic group. Three-vessel calcification was found in 82% of the chronic as compared to only 31% in the acute group. Median TCS was 906 in the chronic and 63 in the acute group. The main clinical application of these two studies (3,4) is the contribution of DHCT to the better understanding of the CAC characteristics and their potential as predictor of ischemic coronary events. While interventional procedures are related to higher amounts of CAC, many of the acute events occur against a background of minor or mild calcifications. This should draw attention to the malignant potential of the underlying atheromas presented by minor CAC. Furthermore it is essential to distinguish between acute and interventional events when the prognostic significance of CAC is assessed.

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PREDICTION OF ANGIOGRAPHIC OBSTRUCTIVE CAD When compared to coronary angiography, the presence of CAC determined by DHCT (measured as total coronary score >0) indicates the presence of obstructive CAD with a sensitivity of 91% and specificity of 52% in one study (5) and 88 and 52% respectively in another study (6). The relatively low specificity reflects the presence of CAC in non- or mildly protruding atheromas within the vessel wall. In fact, the specificity of CT is low only when angiography is considered the gold standard. The truth is that patients who have CAC detected by CT and normal angiograms have false-negative angiograms rather than false-positive CT scans. Sekiya and colleagues showed that these patients have coronary atherosclerosis with reduced ventricular function and coronary reserve (7). The accuracy of DHCT for the diagnosis of angiographically obstructive CAD is similar to that obtained by electron beam CT (EBCT), as indicated in a meta-analysis by Brahmajee and colleagues (8). These authors pooled 1662 patients from nine studies and found a pooled sensitivity of 92.3% and pooled specificity of 51.2%.

CONTRIBUTION OF DHCT IN CHEST PAIN EVALUATION Chest pain is one of the most frequent reasons for referring patients to cardiac evaluation. The diagnostic procedures in many of these patients are directed at excluding the presence of obstructive CAD. We found that for this indication, DHCT is particularly helpful as a first-line diagnostic procedure in equivocal clinical situations. However, in order to maximize the clinical benefits of this diagnostic tool and to avoid unnecessary costs and irradiation, it is essential to define the proper criteria for referring patients for coronary calcium CT. Our experience in this field can be summarized as follows: CT for Chest Pain Evaluation Highly Recommended: • When CAD is not yet diagnosed • Chronic chest pain • Atypical chest pain • Equivocal results of stress tests, thallium, or echo stress • In patients unable to undergo stress test • In patients older than 50 yr, particularly women Less Useful in Patients With: • Known CAD • Acute chest pain syndrome • Typical AP in men • Unequivocal positive stress test or thallium scintigraphy results

We evaluated the prevalence and score of CAC in patients categorized by chest pain type and by gender, and their value in determining which patients with chronic chest pain are optimal candidates for coronary artery calcification scoring with DHCT (9). We found CAC in 87% of men with typical AP compared to only 52% of those with atypical chest pain. This difference was less pronounced in women—54% in women with typical AP vs 44% in those with atypical chest pain. This prevalence of CAC is in accordance with the estimated prevalence of angiographic CAD in patients with AP and atypical chest pain: 90% of the men and 60% of the women with typical

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AP had angiographically obstructive CAD, compared to 70% in men and 40% in women with atypical chest pain (10). We could conclude that using DHCT for excluding coronary calcium yields the best results in middle-aged and elderly patients with chronic atypical chest pain. CHEST PAIN IN WOMEN

Women have higher rates of false-positive ECG and thallium stress tests. They also show poor predictive value of anginal pains for the prediction of angiographically obstructive coronary disease. Moreover, women have a higher likelihood of alternative mechanisms of chest pain, making the diagnosis of CAD even more difficult than in men. Therefore, chest pain in women still poses a diagnostic challenge. The value of exercise electrocardiography as well as thallium scintigraphy have been questioned in women as a result of the higher frequency of false-positive results (11). The demonstration of normal perfusion by radionuclide test, however, is not always predictive of the absence of CAD or future coronary events (12). We studied 48 symptomatic women (mean age 65 ± 5 yr) referred for coronary angiography because of typical angina, or atypical chest pain with a positive exercise or thalium scintigraphy test (13). Women with angiographically normal coronary arteries had lower TCS than those with CAD, 5.7 ± 11 vs 580 ± 634, respectively. Seven women with angiographically normal CAD demonstrated mild coronary calcification (TCS <50). Of the 11 women without CAC, none had CAD. The absence of CAC on DHCT scans in women >60 yr is highly predictive of normal coronary arteries with 61% sensitivity, 100% specificity, and 85% accuracy. DHCT provides a rapid and reliable noninvasive tool for the diagnosis of normal coronary arteries and may spare unnecessary invasive intervention in a great number of elderly female patients, as well as significant cost savings. In another study we further evaluated the contribution of DHCT for the detection of diseased coronary arteries in women with anginal pain, positive exercise test, and angiographically normal coronary arteries—“Syndrome X” (14). Eighty-one consecutive women (mean age 64 yr) referred to coronary angiography for chest pain evaluation underwent DHCT. They were divided into three groups according to stress test and angiographic results: Group 1, the “Normal,” had a normal exercise test and angiographically normal coronary arteries; Group 2, “Syndrome X,” were those with abnormal exercise test and normal coronary arteries; Group 3, the CAD group, comprised women with at least one angiographically diseased vessel. The prevalence of coronary calcification among Syndrome X patients was 63% compared to 96% in women with CAD and 22% in the normal group. The lowest values of TCS were obtained for the normal group. Significantly higher values were found for Syndrome X group, and the highest for the CAD group. This study demonstrates that the majority of women over 50 yr with Syndrome X exhibit calcific coronary atherosclerosis on DHCT. These changes of the coronary artery wall may lead to altered endothelial-dependent vasomotion and reduced coronary flow reserve (15). We believe, therefore, that women with Syndrome X having CAC at DHCT should receive anti-atherosclerotic and probably anti-ischemic therapy.

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In many of our patients, DHCT helped the clinician to achieve the accurate diagnosis, as in the following examples: Case 1—A 58-yr-old asymptomatic subject. He used to perform an ECG stress test each year as a part of an annual check-up program. He has no other risk factors. During the last 6 yr his stress test revealed ST changes, which were interpreted by the cardiologists who performed the tests as false positive. The patient was referred for coronary scan, revealing extensive calcification of the left circumflex artery (Fig. 2). A thallium stress test was than performed, revealing ischemic perfusion defect at the corresponding site. Coronary angiography was recommended. A 90% obstruction of proximal left circumflex was found, which has been successfully opened (Fig. 3A,B). Comments: This case demonstrates the potential of DHCT in the differentiation between false-positive ECG stress test and true silent ischemia: The target patients are those with or without chest pain who have a positive stress test but a normal thallium scan, or inconclusive tests. The differential diagnosis between false and true ischemia is easier if the clinician knows the coronary calcium score of the patient. The presence of extensive calcification, as shown in this case, favors the presence of obstructive CAD and strengthens the indication for coronary angiography. Case 2—A 63-yr-old woman. She has hypercholesterolemia and positive family history for CAD. The patient complained of retrosternal chest burning pain and discomfort for 6 yr. She has diaphragmatic hernia. The clinical manifestations raise two main possible origins for her pains: gastric and coronary. She was referred for stress ECG, revealing unequivocal results with 1.5-mm ST depression at high rate. At this point the patient was referred for coronary scanning, upon which no calcium was detected (TCS = 0, Fig. 4A–C). No further cardiac test was done, and no cardiac events were recorded during 5 yr of follow-up. Comments: Accurate diagnosis of angiographically normal coronary arteries in women over 60 yr old can be achieved by DHCT. This clinical application of the test is based on the wellaccepted concept that angiographically obstructive disease is very unlikely in the absence of CAC. Absence of CAC indicates a false-positive ECG stress test and saves the patient from having to undergo coronary angiography. Case 3—62-yr-old male, asymptomatic, without any other risk factors. He underwent a stress test during his routine annual check-up. (Bruce protocol, 10 min, maximal heart rate 156/ min, 12.9 METS). Up-sloping ST depression of 2.5 mm was observed in leads II, III, aVF, V4–V6 without pain. The patient was referred for thallium single photon emission CT (SPECT) by his cardiologist, revealing a suspected small, mild, reversible defect at the distribution of marginal left circumflex. At this point, the cardiologist decided not to order coronary angiography. The patient then consented to undergo DHCT for one of our investigational protocols, revealing very high TCS of 1725 (>95th percentile) with four-vessel calcification, suggesting the presence of obstructive CAD (Fig. 5). Consequently, he was referred for coronary angiography, revealing severe multiple-vessel obstructions with main Lt obstruction of 65%, proximal LAD of 70%, and mid RCA with 85%, leading to a coronary bypass operation.

Fig. 2. Heavily calcific left circumflex (LCX) coronary artery.

Comments: This case demonstrates a failure of the stress ECG and thallium SPECT to correctly estimate the severity of CAD. The role of a high coronary calcium score as an indicator of obstructive CAD is emphasized: the DHCT results prompted the cardiologist in this case to perform coronary angiography, which led to the diagnosis of multiple obstructive lesions and resulted in a coronary bypass operation. It should be remembered, however, that most of the patients with obstructive plaques are symptomatic. According to our experience, the estimated prevalence of extensive CAC in asymptomatic subjects ages 40–60 yr is approx 5%. Case 4—A 55-yr-old male. Asymptomatic, current smoker. He walks 10 km daily. He performs an annual stress ECG test during a routine check-up. He completed 17 min of the Bruce protocol up to the maximal predictive heart rate without any limiting symptoms or ECG ischemic changes. He consented to undergo DHCT for one of our investigational protocols. Extensive calcification was found, with TCS = 1350 (Fig. 6A–C). Consequently, he was referred for thallium SPECT, which was completely normal; further diagnostic procedures were not recommended. During 2 yr of follow-up, the patient remained asymptomatic and has not sustained a coronary event. Comments: This case demonstrates that extensive CAC may be present without any clinical signs of obstructive CAD. An angiographically patent lumen may be observed despite the presence of extensive CAC within the vessel wall. This can be explained by the Glagov remodeling phenomenon (16). The presence of extensive calcification (above the 90th percentile) in asymptomatic subjects requires thallium stress test. If thallium is normal, coronary angiography is not recommended. Case 5—A 75-yr-old woman, hypertensive and hypercholesterolemic. She complained of chest pain for 15 yr and has deep negative T waves in the precordial leads of her ECG. Echocardiography revealed concentric LVH. Her cardiologist

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Fig. 3. Heavily calcific left circumflex coronary artery (see Fig. 2) led to angiography, which revealed >90% obstruction at the corresponding portion of the vessel (A). Successful angioplasty was performed (B).

Fig. 4. Coronary vessel without calcifications. (A) Main left coronary (main LCA) and left anterior descending (LAD) arteries. (B) Proximal right coronary artery (RCA). (C) Distal RCA.

suspected a concomitant obstructive CAD with previous silent non-q-wave MI. He recommended thallium SPECT, which was nonconclusive with a small perfusion defect, interpreted as breast attenuation artifact. At this point the cardiologist considered coronary angiography. We suggested performing a DHCT. The scan was done and revealed no CAC (Fig. 7); further diagnostic tests were not recommended. The patient has now completed 6 yr of follow-up and has not sustained a coronary event. Comments: This case emphasizes the negative predictive value of DHCT. The absence of CAC in a 75-yr-old woman made the diagnosis of angiographically obstructive CAD very

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Fig. 5. Three-dimensional reconstruction of the heart with extensive coronary calcification. MLCA, main left coronary artery; LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery.

Fig. 6. Extensive coronary calcifications may be present without symptoms, as in this 55-yr-old male patient. (A) Left anterior descending (LAD). (B) Left circumflex coronary artery (LCX). (C) Distal right coronary artery (RCA).

unlikely. The deep negative T waves of the woman reflects her left-ventricular hypertrophy. Coronary CT may also help the diagnosis of co-existing CAD in patients with atrial fibrillation (17) or CLBBB. The main limitations of the use of DHCT for chest-pain evaluation

are in patients younger than 50 yr who might have noncalcific CAD, and in cases of acute chest pain, which may be the consequence of soft-plaque rupture. (In our studies, up to 19% of patients with first AMI had no CAC on DHCT; the younger the patient, the higher this percentage may be.)

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TRACKING THE PROGRESSION OF THE CORONARY ATHEROSCLEROTIC PROCESS DHCT CAN ACCURATELY TRACK THE CALCIUM PROGRESSION

Fig. 7. Absence of calcium excludes the presence of concomitant obstructive coronary artery disease in a 75-yr-old female with hypertrophic cardiomyopathy. LAD, left anterior descending artery.

In summary: Coronary calcium scoring can help the clinician to confirm the presence of CAD and to inform him about its extent. Further diagnostic procedures can be used more efficiently, reducing costs by saving unnecessary procedures. The test is useful to exclude obstructive CAD in patients older than 50 yr with chronic atypical chest pain, particularly in women, due to their higher prevalence of false-positive stress tests.

DIAGNOSIS OF ISCHEMIC ETIOLOGY OF DILATIVE CARDIOMYOPATHY OF UNKNOWN ORIGIN The etiology of dilative cardiomyopathy (DCMP) is important for both therapeutic and prognostic implications, but the differential diagnosis may still be difficult after evaluation of the clinical data and generally requires coronary angiography. We have demonstrated that the presence or absence of CAC on DHCT provides a useful tool in differentiating between ischemic and nonischemic DCMP in middle-aged patients (18). Thirty-two consecutive patients with DCMP who underwent coronary angiography were scanned. Thirteen patients (mean age 60 ± 8) had nonischemic DCMP with normal coronary arteries, whereas 19 (mean age 60 ± 6) exhibited ischemic DCMP with at least two obstructed vessels. CAC was found in all patients with ischemic DCMP and was absent in 12 of the 13 with nonischemic DCMP. The presence of CAC on DHCT can thus identify ischemic DCMP with a sensitivity of 100%, specificity of 92%, and total accuracy of 97%, providing a reliable noninvasive tool for the differential diagnosis of ischemic from nonischemic DCMP. The results of this study were reproduced by Budoff et al. on EBCT (19).

Studies of the progression of coronary atherosclerosis have hitherto been limited to invasive angiographic techniques among symptomatic patients. The ability to quantify coronary atherosclerosis by a simple noninvasive technique provides clinicians and researchers with a simple method to monitor the effect of anti-atherosclerotic treatment. We have demonstrated the accuracy of DHCT in tracking the progression of CC as measured during a 3-yr follow-up (20) (Fig. 8). Ninety-four of the 246 patients who entered the study had no calcium (TCS = 0). Among the 152 with calcium (TCS >0), 33 had minimal amounts of calcium (TCS 1–9), and 119 had a total score >9; 60 of them (50%) had baseline TCS <100 and 75% had TCS <250. The mean TCS of the patients with calcium increased significantly each year from 245 at baseline to 288, 322, and 349 at the end of the first, second, and third year of follow-up (p for trend <0.01). This corresponds to a percent change from baseline TCS of 33, 71, and 117% respectively. This progression of calcium was not related to age, sex, or any other risk factor by univariant analysis. The incidence of 3 yr progression of calcium was almost three times higher among the patients with calcium at baseline compared to those without calcium: 70% (106/152) compared to 28% (26/94). All the 33 patients with baseline minimal amounts of calcium (TCS <9) had detectable calcium at follow-up, with increasing mean TCS from 3.8 ± 0.45 to 14.9 ± 2.7. We found that baseline TCS is a very strong predictor of the follow-up TCS. This was found by other researchers who used EBCT (21) and described by Yoon and colleagues (22) as “calcium begets calcium.” CLINICAL SIGNIFICANCE OF CAC PROGRESSION

We investigated the hypothesis that a higher progression rate of CAC is related to cardiac events, in a cohort of hypertensive patients who were followed during a period of 3 yr (23). One hundred sixty-eight consecutive hypertensive patients who underwent annual CT scans over a 3-yr period were selected among the 547 participants of the INSIGHT calcification side arm study (24). Patients were divided into three groups: 1. Asymptomatic with prominent atherosclerotic risk factors (n = 116). 2. Patients with clinical CAD at baseline (n = 28) (“Stable CAD”). 3. Patients who sustained a coronary event (n = 24) during follow-up (“Event”).

Clinical CAD was defined as previous myocardial infarction, typical AP with positive stress test, or positive coronary angiography (>50% lumen obstruction in at least one epicardial vessel). Coronary events were AMI, unstable AP, sudden death, hospitalization for increased preexisting angina, coronary angiography, coronary angioplasty, or coronary bypass operation. The progression of CAC was calculated as percent increase from baseline total coronary calcium score. A significant annual progression of total coronary calcium score was

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Fig. 8. Progression of coronary calcium. Two spotty lesions at baseline in the proximal right coronary artery (RCA) (A), with significant increase after 3 yr (B).

observed within each of the three study groups (p < 0.01). Both patients with stable CAD and asymptomatic patients with a stable rate of CAC developed a coronary event. There was a higher progression rate at the end of follow-up of patients who sustained a coronary event compared to those who did not: 180% vs 124 in asymptomatic and 118% in the group of stable CAD (p < 0.05). Prevalence, extent and annual progression of CAC in patients with documented CAD are significantly higher than in asymptomatic subjects. The mean annualized percent of progression in asymptomatics is 15%, and three times higher (47%) in patients with CAD. These results sharpen the importance of excluding patients with documented CAD from studies designed to evaluate interventional effects and prognostic value of CAC in asymptomatic populations.

PROGRESSION UNDER INTERVENTION

Using DHCT we have been able to demonstrate different progression rates of CAC over a 3-yr period, in hypertensive patients treated by nifedipine once daily vs co-amilozide following the protocol of the INSIGHT study (24). A total of 201 patients with a TCS > 9 at the onset of the study underwent an annual DSCT for 3 yr. Coronary calcium progression was significantly lower in the group treated by nifedipine as compared to the co-amilozide group, 40% vs 78% at the third year. PROGRESSION IN TRANSPLANTED HEARTS

Tracking the progression of allograft atherosclerosis in heart transplant recipients is currently accomplished using invasive techniques. We used DHCT to track CAC progression in 24 consecutive heart transplant patients (25). The first scan was performed 1.9 ± 1.3 yr after transplantation. After 2 yr of fol-

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low-up, 4 died and the remaining 20 patients underwent a second scan. The incidence of CAC at the first scan was 4.2% and increased to 40% at the second scan. We could identify very mild new spotty lesions with a mean TCS of 6.7. Our findings confirm the results of previous studies done by Barbir and colleagues using EBCT on 102 heart transplant recipients. They found calcific lesions in 45% of the patients with a similar minimal amount of CAC (26). Spiral CT can be a noninvasive alternative for the detection of newly developed atherosclerotic changes in heart transplant recipients. The delayed appearance of CAC in heart transplants suggests that CT should be done no less than 2 yr after transplantation.

10.

SUMMARY

12.

Evaluation of chest pain, diagnosis of false-positive ST changes upon stress test, diagnosis of obstructive CAD, and evaluation of the effect of anti-atherosclerotic treatment constitute a major part of the daily clinical practice. We have demonstrated that a comprehensive use of DHCT substantially contributes to these topics. The accordance between data obtained from DHCT and EBCT devices in many of these subjects indicates that for clinical practice, coronary calcium detection and measurement is relevant regardless of the device or the technique used. We strongly believe that our and others’ results demonstrate the usefulness of the new multislice spiral CT devices. The differentiation between minimal, mild, moderate, and extensive CAC is universal. The numerical scale of each category should be individualized to each specific device after the most accurate and reproducible protocol has been defined. Essential questions such as whom to refer for this test, for which diagnostic question, how to interpret the results, and the contribution of the test for better treatment of the patients should be further discussed.

REFERENCES 1. Stary HC. The development of calcium deposits in atherosclerotic lesions and their persistence after lipid regression. Am J Cardiol 2001;88:16–19 2. Fuster V. Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation 1994;90:2126–2146. 3. Shemesh J, Stroh CI, Tenenbaum A, et al. Comparison of coronary calcium in stable angina pectoris and in first acute myocardial infarction utilizing double helical computerized tomography. Am J Cardiol 1998;81:271–275. 4. Shemesh J, Apter S, Itzchak Y, Motro M. Coronary calcification compared in patients with acute versus in those with chronic coronary events using dual-sector spiral CT. Radiology 2003;226:483–488. 5. Shemesh J, Apter S, Rozenman J, et al. Calcification of coronary arteries: detection and quantification with double helix CT. Radiology 1995;197:779–783. 6. Broderick LS, Shemesh J, Wilensky RL, et al. Measurement of coronary artery calcium with double helical CT compared to coronary angiography: evaluation of CT scoring methods, interobserver variation, and reproducibility. AJR Am J Roentgenol 1996;167: 439–444. 7. Sekiya M, Mukai M, Suzuke M, et al. Clinical significance of the calcification of coronary arteries in patients with angiographically normal coronary arteries. Angiology 1992;43:401–407. 8. Brahmajee KN, Saint S, Bielak LF, Sonnad SS, Peyser PA, Rubenfire M, Fendrick M. Electron-beam computed tomography in the diag-

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nosis of coronary artery disease: a meta-analysis. Arch Intern Med 2001;161:833–838. Shemesh J, Weg N, Tenenbaum A et al. Usefulness of spiral computed tomography (dual-slice mode) for the detection of coronary artery calcium in patient with chronic atypical chest pain, in typical angina pectoris, and in asymptomatic subjects with prominent atherosclerotic risk factors. Am J Cardiol 2001;87:226–228. DeSanctis RW. Clinical manifestations of coronary artery disease: chest pain in women. In: Wenger NK, Speroff L, and Packard B (eds), Cardiovascular Health and Disease in Women. Le Jack Communications, Greenwich, CT: 1993;67. Hung J, Chaitman BR, Lam J, et al. Non-invasive diagnostic test choices for the evaluation of coronary artery disease in women: a multivariate comparison of cardiac fluoroscopy, exercise electrocardiography, and exercise thallium myocardial scintigraphy. J Am Coll Cardiol 1984;4:8–16. Niemeyer MG, Van Der Wall EE, Kuyper AF, et al. Discordance of visual and quantitative analysis regarding false negative and false positive test results in thallium-201 myocardial perfusion scintigraphy. Am J Physiol Imaging 1991;6:34–43. Shemesh J, Tenenbaum A, Fisman EZ, et al. Absence of coronary calcification on double helical CT scans: predictor of angiographic normal coronary arteries in elderly women? Radiology 1996;199: 665–668. Shemesh J, Fisman EZ, Tenenbaum A, et al. Coronary artery calcification in women with syndrome X: usefulness of double helical CT for detection. Radiology 1997;205:697–700. Gage JE, Hess OM, Murakami T, et al. Vasoconstriction of stenotic coronary arteries during dynamic exercise in patients with classic angina pectoris: reversibility by nitroglycerin. Circulation 1986;73: 865–876. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. New Engl J Med 1996:316:1371–1375 Stroh CI, Shemesh J, Motro M. Using fast CT to exclude CAD in elderly women (60 and above). N Engl J Med 1996;335 (8):595. Shemesh J, Tenenbaum A, Fisman EZ, et al. Coronary calcium as a reliable tool for differentiating ischemic from nonischemic cardiomyopathy. Am J Cardiol 1995;77:191–194. Budoff MJ, Shavelle DM, Lamont DH, Kim HT, Akinwale P, Kennedy JM, Brundage BH.Usefulness of electron beam computed tomography scanning for distinguishing ischemic from nonischemic cardiomyopathy. J Am Coll Cardiol 1998;32(5):1173–1178. Shemesh J, Apter S, Stroh CI, Itzchak Y, Motro M. Tracking coronary calcification by using dual-section spiral CT: a 3-year followup. Radiology 2000;217:461–465. Schmermund A, Baumgart D, Möhlenkamp S, et al. Natural history and topographic pattern of progression of coronary calcification in symptomatic patients: an electron beam CT study. Arterioscler Thromb Vasc Biol 2001;3:421–426. Yoon HC, Emerick AM, Hill JA, Gjertson DW, Goldin JG. Calcium begets calcium: progression of coronary artery calcification in asymptomatic subjects. Radiology 2002;224:236–241. Shemesh J, Apter S, Stolero D, Itzchak Y, Motro M. Annual progression of coronary artery calcium by spiral computed tomography in hypertensive patients without myocardial ischemia but with prominent atherosclerotic risk facors, in patients with previous angina pectoris or acute myocardial infarction which healed, and in patients with coronary events during follow-up. Am J Cardiol 2001; 87:1935–1937. Motro M, Shemesh J. Calcium channel blocker nifedipine slows down progression of coronary calcification in hypertensive patients compared with diuretics. Hyprtension 2001;37:1410–1413. Shemesh J, Tenenbaum A, Stroh CI, et al. Double helical CT as a new tool for tracking of allograft atherosclerosis in heart transplant recipients. Invest Radiol 1999;32:503–506. Barbir M, Lazem F, Bowker T et al. Determinant of transplanted coronary calcium detected by ultrafast computed tomography scanning. Am J Cardiol 1997;79:1606–1609.

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Detection and Quantification of Calcified Coronary Plaque With Multidetector-Row CT J. JEFFREY CARR, MD, MSCE

INTRODUCTION Multidetector-row computed tomography (MDCT) has rapidly developed into a powerful tool for noninvasive measurement of calcified plaque in the coronary arteries over the past decade. Identification and quantification of coronary artery calcifications (CAC) with X-ray devices is well established in the literature with chest radiographs, fluoroscopy, computed tomography (CT without electrocardiogram [ECG] gating) and cardiac CT (electron beam CT [EBCT], helical CT , and MDCT with cardiac gating) (1–6). Calcified plaque is an established component of coronary atherosclerosis, and radiographic techniques are highly sensitive to calcified atherosclerotic plaque (1,7). The presence of calcified plaque documents the presence of subclinical atherosclerosis in the coronary artery. Calcified plaque is an active and regulated process occurring in the vessel wall, with pathways similar to those of bone metabolism (8,9). As of 2003, two consensus documents (1,10) concerning cardiac CT and the recommendations of the Prevention V Conference (11) are available to guide clinical application. The results of several large epidemiological studies, as well as pharmaceutical trials, will become available during the next five years and will provide new information to guide the medical community and society at large as to the appropriate utilization of CAC screening in the population. Cardiac CT is rapidly transitioning from a research tool with modest clinical application to a diagnostic test integral in our management of cardiovascular disease. There is increasing evidence that cardiac CT applied to measuring CAC will be effective in the risk stratification of individuals asymptomatic for cardiovascular disease (CVD), as will be discussed later in this chapter. The rapid development of the cardiac-gated MDCT techniques was made possible through the pioneering work performed with EBCT in the 1980s and 1990s. Technological advances in engineering, manufacturing, and computer sciences made possible the current-generation MDCT systems. The strengths of cardiac CT and, specifically, MDCT, are detailed in the technical chapters, but are based on high spatial resolution, volumetric coverage, high temporal resolution, rapid scan times, high patient productivity, robust protocols, From: Contemporary Cardiology: CT of the Heart: Principles and Applications Edited by: U. Joseph Schoepf © Humana Press, Inc., Totowa, NJ

consistent results, and high patient acceptance. In this chapter we will review the history of MDCT for the measurement of CAC, discuss the technical aspects and various implementations of MDCT protocols for measuring CAC, and review scientific results published and in-progress with cardiac CT and MDCT specifically.

EVOLUTION OF HELICAL CT TO CARDIAC-GATED MDCT The ability to identify the heart and calcifications related to the coronary arteries was noted even with early-generation CT scanners, despite insufficient temporal resolution to stop cardiac motion (12,13). The motion of the heart blurred anatomic detail related to the coronary arteries and cardiac chambers. The development of slip-ring CT technology, which enabled spiral or helical CT scanning, dramatically improved the temporal resolution of mechanical CT systems. Increased gantry speed provided improved temporal resolution and greater scan coverage per unit time, which facilitated protocols incorporating suspended respiration (14). When CT gantries capable of 1 s were possible, the nongated ECG scans through the chest clearly demonstrated improved cardiac and coronary morphology, and strategies for quantifying CAC were developed (2,15,16). Cardiac gating of helical CT exams using a helical acquisition was first coupled with low-pitch overlapping reconstruction algorithms designed to maximize temporal resolution and create multilevel, multiphase images of the entire coronary circulation. (17). Synchronized recording of the ECG tracing during the scan acquisition allowed the images to be aligned with the ECG tracing of cardiac activity. This retrospective ECG gating was performed after the scan was acquired (i.e., postexam processing) on a computer workstation, and allowed the user or computer algorithm to select the appropriate diastolic phase image for measuring CAC (Fig. 1). The introduction of the 0.8-s gantry rotation and higher heat unit X-ray tubes made possible a more clinically feasible study with further improved image quality. The 0.8-s gantry rotation resulted in cardiac imaging with a temporal resolution of 520 ms per image, and the high heat unit tube meant that the scans could be obtained in clinical practice without extended wait periods for tube cooling. This first-generation cardiac-gated helical CT technique allowed scanning the entire heart in a single breathhold ranging from 30 to 50 s, depending on heart rate, which determined the helical pitch (4).

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Fig. 1. Retrospective gating with a single-slice helical CT system. The image is from a retrospectively gated helical scan performed in June of 1999 (General Electric Medical Systems)—CTi, with 0.8-s gantry, SmartScore calcium scoring package on the Advantage Windows workstation). Overlapping images are reconstructed throughout each cardiac cycle, represented by the gray diamonds. An automated selection algorithm picks the diastolic phase image at a preprogrammed percentage of the cardiac cycle (red diamond) and is displayed in the image window below the electrocardiogram (ECG) tracing. As discussed in the text, images are obtained throughout the cardiac cycle, resulting in significantly higher exposure than in a prospectively triggered sequential protocol. Modern multidetector-row CT systems obtain multiple channels of data simultaneously (4, 8, 12, or 16, depending on model). However, like the single-slice helical CT system, the helical reconstruction algorithm requires data throughout the scan, and thus the X-ray tube is on continuously. ECG dose modulation is available and reduces tube current during systole to improve the dose profile of the study. However, even with tube modulation, prospective triggering results in the lowest dose profile while maintaining comparable image-quality factors. Calcified plaques are demonstrated in the left anterior descending coronary artery.

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The studies comparing the single-slice scanners with ECG gating demonstrated high correlation and good agreement between calcium scores obtained with that generation of EBCT systems (C150) and the single-slice helical CT systems (3,4,18–20). This new capability for helical CT came with limitations. First, the overlapping reconstructions resulted in a large number of images—typically 450–600 images per scan series. The large number of images required significant computational resources to reconstruct the images, and this process would often have to be completed offline to reduce impact on patient throughput on the CT scanner. The scans also tended to result in relatively long breath-holds, ranging from 35 to 50 s. With the single-slice helical CT, the breath-hold time was dependent upon the patient’s heart rate, which was used to set the speed of the CT couch as it moved the patient through the scanner. The single-slice helical CT exam was dose-inefficient in that the patient was irradiated for the entire cardiac cycle, but only a few cardiac phases at most were utilized for calcium scoring. Prospective ECG triggering was developed and tested on these systems, but the application was limited by long scan times, which required multiple breath-holds to image the entire heart (3). Nonetheless, single-slice helical CT systems operating with effective temporal resolutions of 520 ms demonstrated the capability of mechanical CT scanners to accurately and reproducibly measure CAC with comparable measurement error to EBCT. Direct comparison of helical CT and EBCT with individuals receiving paired scans on each system demonstrated no statistically significant difference in the interexam or intraobserver variability when using the standard 130-Hounsfield unit (HU) threshold (21). The foundation developed for single-slice helical CT was critical for developing cardiac applications, reconstruction algorithms, ECG and non-ECG gating strategies, and postprocessing for the revolution in CT—the introduction of multislice scanners.

MDCT SYSTEMS—APPLICATION TO CORONARY CALCIUM MEASUREMENT The introduction of the four-channel MDCT systems created new possibilities for cardiac imaging. The ability to acquire four 2.5-mm slices results in covering 10 mm along the z axis with each heart beat. The entire heart, typically 120 mm in z axis length, could be imaged with only 12 movements of the CT couch. For the first time the entire heart could be covered with prospective ECG gating in a clinically acceptable breath-hold time. The initial release of the four-channel MDCT systems had gantry rotations of 0.8 s, although this was followed by systems with gantry rotation speeds of 0.5, 0.42, and 0.4 s, resulting in temporal resolutions ranging from 520 to 240 ms when scanning in the cardiac mode (i.e., partial scan reconstruction). The MDCT scanner is operated in the sequential scan mode (on some systems this is called axial or cine scan mode), resulting in significantly less radiation exposure than the helical approach utilizing retrospective ECG gating. This approach is fundamentally identical to calcium screening protocols implemented with EBCT systems that also utilize a “stepand-shoot” sequential scan technique.

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The basic operation of a MDCT system for sequential CAC study with prospective ECG gating is the same whether it is 4, 8, or 16 slices. The operator prescribes the start and end locations based on the scout image of the thorax. The MDCT scanner moves the CT couch so that the first block of 4, 8, or 16 images is appropriately positioned inside the gantry. The scan sequence is started by the breathing instructions, and the first block of images is obtained at the prescribed offset from the R wave on the ECG. In the sequential mode, the X-ray beam is on for only a very brief exposure at each level. For a 0.5-s gantry system this time is slightly more than the number of views required to reconstruct an image, and is typically in the range of 330–360 ms, depending upon manufacturer. For a General Electric LightSpeed™ 8 or 16 MDCT with a 0.5-s gantry, the X-ray exposure time is only 2 s for the entire scan. During the majority of the 10–20-s scan time, the X-ray tube is off because the CT couch is moving to the next location or the CT is waiting for the appropriate cardiac phase. Upon completion of the first set of images, the CT couch then moves the patient to the next block of scans along the z axis. This movement occurs during the second cardiac cycle, which then allows the second block of slices to be obtained during the third cardiac cycle of the breath hold. This sequence of acquiring and skipping a heartbeat continues until all the prescribed scan locations have been completed. As of 2003, MDCT systems use various detector arrays with a length along the z axis of 20 mm. For the MDCT(4) systems, a 4 × 2.5-mm slice protocol uses the center 10 mm of the detector. The introduction of the MDCT(8) and MDCT(16) systems allowed scans for coronary calcium using an 8 × 2.5-mm configuration, thus utilizing the entire 20-mm width of the detector array. A comparison of MDCT systems is presented in Table 1. The direct benefits of this for coronary calcium scanning are the reduction in reduced breath-hold time to 10–20 s as opposed to 20–40 with MDCT(4). Only six CT couch translations and thus only 6 cardiac cycles—as opposed to 12 with MDCT(4)—are needed to image the entire heart, which improves the image quality by reduced variability related to cardiac beat-to-beat variations, improved slice registration along the z axis, and reduced patient dose through improved dose efficiency. One way to conceptualize prospective ECG gating with MDCT is to mentally construct the “ideal” CT device, in which a detector covers the entire heart. This system might have 48 channels or rows (i.e., capable of 2.5-mm slices × 48 levels = 128-mm detector) through the use of either a panel or dramatically expanded matrix array detector (22,23). To measure coronary calcium with a similar protocol to today’s CT systems, the hypothetical “MDCT(48)” scanner would operate in the sequential mode and acquire 48 slices, each 2.5 mm thick, within a single heart beat. If we assume no further improvement in gantry rotation speeds beyond 0.4 s and utilize the current partial scan reconstruction algorithm, then scan acquisition and breath-hold time would be 250 ms! The entire coronary arterial tree would be acquired within a 250-ms phase of a single cardiac cycle, and no movement of the patient by the CT couch

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Table 1 Comparison of MDCT Multislice Capability on Scan Time—Sequential Scan Mode With Prospective ECG Gating Multislice capability

Slice thickness (mm)

Slab thickness (mm)

Slabs per 120 mm coverage

Scan time (s)

1 4 8 8 or 16 20 48

2.5 2.5 2.5 2.5 or 1.25 6 2.5

2.5 10 20 20 10–20 120

48 12 6

80–160 20–40 10–20

1

0.24

Slab thickness roughly corresponds to beam collimation; however, the beam must be slightly wider than the nominal detector configuration. Current 16-channel systems are limited in their z axis coverage by the 20-mm width of the detector. These systems can typically acquire in either an 8-slice mode (8 × 2.5 mm) or 16-slice (16 × 1.25 mm) with increased spatial resolution in the slice direction (z axis). The hypothetical 48-slice MDCT system is provided as an example of how the increasing size of the detector along the z axis will impact future cardiac CT protocols. Numerous technical challenges remain to be solved before this type of system or some variant is ready for clinical applications.

would be required. “Sequential” would be a misnomer, since only one block or set of 48 images would be obtained. By acquiring all levels or slices of the coronary tree in a single heartbeat, slice misregistration related to beat-to-beat coronary motion, breath-holding, and voluntary patient motion would be eliminated. A more likely scenario is that this enhanced imaging capability would be coupled with more sophisticated reconstruction algorithms, providing either enhanced temporal resolution or increased coverage of cardiac motion (multiphase imaging) or both to varying degrees. MDCT systems will continue to rapidly develop new capabilities focused on cardiac imaging, based in large part on the intense global competition between CT manufacturers. Based on the rapid developments with CT of the past decade, it is foolhardy to speculate what capabilities may be available to cardiac imagers even in the near future from the descendents of today’s MDCT systems. It is clear that future MDCT systems will incorporate enhanced resolution both temporal and spatial, greater coverage of the heart, new methods for cardiac motion compensation, dose reduction techniques, scan reconstruction and postprocessing applications specifically designed for cardiac imaging. What remains unknown is when, and what impact these advances in cardiac imaging with CT will have on clinical management.

MEASURING CALCIFIED CORONARY PLAQUE WITH CARDIAC CT In quantifying the amount of calcified plaque in the coronary arteries, the CT system is acting as a measurement device. Something common to all measurement techniques is the presence of measurement error. Comparison of two measurements will by definition incorporate the combined errors of the two measurements. The problems associated with comparing a new technique to an established technique are well documented in medical and statistical literature (24,25). Accuracy is defined as how well the instrument is calibrated to the true value of the object being measured. Precision indicates the degree of refine-

ment of the reported value. Thus a measurement can have high precision (alternatively, highly reproducible or refined), providing nearly the same value on multiple measurements but biased from the true value. Likewise a device can be well calibrated but have significant variability, resulting in decreased precision. Most importantly, the degree of accuracy and precision must be appropriate for the desired task. Fortunately, cardiac CT can measure plaque burden with high accuracy and good precision in the range of values for which clinical decisions are likely to be made, based on existing outcomes data. Specifically, EBCT and MDCT have extremely good measurement characteristics for plaque burden above Agatston scores of 50. More problematic, as will be discussed later, are the low scores, where detection and image noise issues have been shown to negatively impact the ability to measure calcified plaques. Likewise, changes in calcium scores over short time intervals can easily be shown in groups of patients, with reasonable statistical power; however, tracking change in CAC in an individual over a year requires significantly greater precision and accuracy. CT was developed as a medical imaging device, with less emphasis on quantification of the X-ray attenuation values (a.k.a. CT numbers or HU). The CT attenuation values extend from –1000 to +4000. CT number 0 is calibrated to water, –1000 to air, +1000 to dense bone, and >1000 to metal objects. Limitations in the CT scanners’ ability to measure small calcified objects were established early in the history of CT, during attempts to quantify calcification in pulmonary nodules. Since this effort, there has been significant improvement in the CT system stability and quality control over the past decade (26). When comparing CT devices (EBCT vs EBCT, MDCT vs MDCT, or EBCT vs MDCT) an understanding of the influences of accuracy and precision are important to understand any observed differences. Significant variability in the measurement of coronary calcium between EBCT systems at the same site maintained and calibrated by the same engineers has been reported with the 130 HU threshold varying between 77.1

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and 136.4 mg/cm3 of calcium hydroxyapatite (27). Likewise, when replicate calcium determinations are performed using EBCT, significant measurement error has been documented. Mean interscan variability using the Agatston scoring method has ranged from 18 to 43%, and there remains debate about the impact of a 40% vs 80% phase for image acquisition (28–32). The nature of the calcium score and the range of values from 0 to greater than 10,000 requires an understanding that the measurement error changes based on the amount of calcified plaque; a more detailed analysis using methods proposed by Bland to determine limits of agreement is indicated and has been performed by some researchers (24,33). Comparable degrees of measurement error, as will be discussed later, have been documented for MDCT. It must be remembered that if one measurement device is labeled the “gold standard,” all comparison instruments will have the error inherent in the gold standard included and in some cases erroneously attributed as error related to the comparison device. The measurement error is related to the physiology of the heart and the size of the calcified plaques we are measuring with the CT systems. Specifically, we are asking the CT system to measure relatively small calcified plaques located on 3-mm or smaller coronary arteries using a slice collimation of 2.5–3 mm, depending on CT system. This results in partial volume averaging of the plaque within or between two slices, which can dramatically alter the CT numbers of the plaque. In addition, motion blurring is present with EBCT and to a greater extent with MDCT. Blurring of the plaque secondary to coronary motion is most common in the right coronary artery, and alters the values of the picture elements (pixels) within a given image. Lastly, detection of calcified plaques is determined by the presence of more signal (information about the plaque and surrounding structures) than noise. Image noise is random by definition and obscures information or signal. The noise in the CT images creates false-positive plaques that cannot be differentiated from true calcified plaques. The impact of image noise on smalllesion detection has been documented with EBCT (34). A limitation of EBCT is the fixed mAs (approx 60). With mAs fixed, image noise increases with thoracic size and degrades image quality in larger patients. The established relation between body size and image noise will creates an erroneous relationship between obesity and CAC (35,36). Since both obesity and CAC are associated with CVD, this results in confounding the true relationship. The ability to alter technique and maintain a constant image quality (i.e., an acceptable level of image noise) is a critical benefit of MDCT techniques for CAC (37,38). There is by definition a trade-off between improved image quality (i.e., less image noise means more signal and more X-ray photons) and increased dose. Thus, image quality should be selected based on the clinical application of the results. Current and likely future clinical recommendations indicate changes in management using significant levels of plaque burden corresponding to Agatston scores ranging from 100 to 400. However, if a percentile approach or progression rates are to be utilized in clinical practice, then these issues become critical and further research into the optimal level of image quality is required.

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STUDIES EVALUATING CALCIFIED PLAQUE MEASUREMENT WITH CARDIAC CT In the studies to date, extremely high correlations have been seen between CT devices for both the amount of calcified plaque and the rank ordering of patients’ calcium burdens. In the initial comparisons of EBCT to single-slice helical CT with ECG gating, the correlation between scores performed on the same individuals was near perfect (R > 0.97), and mean interscan variability was 25% (3,4). In addition, the more conservative nonparametric Spearman’s test of rank order was shown to be extremely high (0.96), and agreement at grouping patients based on Agatston scores of 100, 200, and 400 was 97%, 92%, and 94% respectively. The study by Goldin et al. is the only study to date in which a direct comparison of interscan variability between EBCT and helical CT/MDCT has been performed. In this study, participants had paired scans and calcium measurements on an EBCT (C150) and a GE helical CT system with cardiac gating (0.8-s gantry), and no statistically significant difference in interscan or interobserver variability was found when using the 130 CT threshold and Agatston scoring method. Differences in risk stratification were observed between the two methods. The documented high correlations for both amount of calcium and ordering of calcified plaque burden in these studies indicates that differences in agreement could be improved through calibration of calcium plaque measured by CT to an external standard (4,27). This calibration would reduce systematic bias related to the CT system and further improve agreement. The National Heart, Lung and Blood Institute of the National Institutes of Health is funding the Multi-Ethnic Study of Atherosclerosis (MESA), in which 6800 individuals asymptomatic for CVD have received an extensive CVD exam, including cardiac CT measurement of CAC. MESA exams are performed at six field centers across the United States (39). The participants had replicated measures of coronary calcium made during the baseline CT visit in order to measure interscan variability and to improve the ability to track progression of calcified plaque in subsequent planned exams of the cohort. In MESA, three field centers utilized EBCT (C150) and three MDCT (4-slice). Findings from the baseline exam on cardiac CT interscan variability were presented at the American Heart Association Scientific Session in 2002 (40). After adjusting for mean calcium score and body mass index, there was no significant difference between median interscan variability using the Agatston score (EBCT 22.7 vs MDCT 24.7, p = 0.15) or volume score (EBCT 11.0 vs MDCT 11.9, p = 0.84). The median interscan percentage differences using the Agatston score were 18.1 % (EBCT) and 18.7% (MDCT), and are consistent with the range of interscan variability published for EBCT of 18–43% as well as the result published with MDCT(4) demonstrating interscan variability of 20.4%, 13.9%, and 9.3% for Agatston score, volume, and mass respectively (41). The conclusions we can draw from these data is that the measurement precision of EBCT and MDCT(4) are very similar. The component of the overall observed variability attributable to the CT systems (EBCT vs EBCT, MDCT vs MDCT, EBCT vs MDCT) is small relative to the intrinsic variability present in measuring CAC with existing cardiac CT technology.

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MDCT—CARDIAC-GATED HELICAL ACQUISITIONS FOR CAC MDCT systems can scan in a helical mode and can reconstruct images compensated for cardiac motion using either ECG waveform or the inherent motion of the heart (42–44). These techniques are detailed in other chapters, but evolved directly from the single-slice helical CT retrospective gating described previously (Fig. 1). Although currently used and developed for MDCT coronary angiography, it is clear that these advances in coronary imaging can be applied to measuring calcified plaque in the coronary arteries during a non-contrast-enhanced study. Specifically, the improved spatial and temporal resolution possible with these techniques has already been shown to reduce inter-exam variability from 35% with EBCT using the standard sequential technique and 3-mm slices to 4% with volumetric MDCT using a helical scan with overlapping 2.5-mm slices in controlled testing with a motion phantom of the coronary arteries (45,46). These methods hold significant potential. The increased radiation exposure and limited clinical experience has limited their application to date. Lower-dose methods incorporating mA modulation and low-kV imaging are available, and initial reports have demonstrated promising results (47–49). At this time, prospective ECG gating with a sequential scan acquisition is the preferred standard for clinical use, based on the lower radiation exposure and more extensive clinical and research experience to date. The future application of the helical technique to coronary calcium imaging, although promising, remains to be fully defined and validated for clinical practice.

IMAGE NOISE AND CARDIAC CT Atherosclerosis begins as early as the second decade of life, and includes the formation of small calcified lesions (50). Detection of calcified plaques in the walls of the coronary arteries requires increasing image quality as the size of the plaque becomes smaller. In essence, with CT (EBCT or MDCT) the device is measuring those calcified plaques above the predefined threshold and size criteria configured in the scoring software. These factors are determined not by the pathobiology of atherosclerosis but by the imaging specifications of the CT devices. Individuals with a calcium score of zero represent a range of calcified coronary plaque not measurable by existing CT technologies. Previous authors have suggested lowering the threshold for CT-measurable calcified plaque from 130 to 90 CT units (16). This effectively increases the sensitivity of the CT test for earlier plaque. For helical CT and MDCT systems, this is possible through the ability to maintain sufficient image quality by adjusting the mA or tube current to maintain the signal-to-noise ratio (SNR) at an acceptable level. Without maintaining the SNR, the image quality is degraded to the point that image noise obscures the small, calcified plaques. With EBCT, mAs is fixed. Individuals with increasing thoracic girth have increasing image noise. Image noise can vary on MDCT systems depending upon the technique employed, but typically range between 8 and 16 noise/HU, compared to 24 noise/HU for EBCT. Image noise can be scored as CAC resulting in falsepositive results and inflate the size of true lesions. This relation

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between patient size and image noise with EBCT has been demonstrated to confound the true relation between CAC and obesity (35). Cardiac imaging requires all aspects of image quality (SNR, temporal resolution, contrast-to-noise, and spatial resolution) to be balanced appropriately for the desired task. In the specific case of detecting and quantifying small calcified plaques in the coronary arteries, the critical influence of image noise was established early in the literature with EBCT (34). The epidemic of obesity in industrialized societies and the elevated risk of CVD seen in individuals with the metabolic syndrome (which includes obesity) means that any device that will be used for screening the general population for CVD must be able to handle individuals weighing greater than 100 kg (220 lb) without creating false-positive calcium scores. Maintaining a consistent level of image quality across various patient sizes will significantly improve image quality and the measurement of CAC.

IMPROVED SPATIAL RESOLUTION The continued technological advancement of MDCT systems will allow imaging with increasing spatial resolution in the slice or z direction. Current MDCT-16 systems can provide 1.25-mm slices by 16 levels simultaneously with protocols reconstructing 2.5 mm × 8 levels at no increased dose or exposure to patient. With increasing spatial resolution, issues related to dose and SNR become increasingly important. Fundamentally, improved spatial resolution will allow more accurate measurement of small coronary plaques (Fig. 2). If the CT technique and radiation exposure is held constant, by definition greater image noise will be present on the thinner 1.25-mm images, when compared to the 2.5-mm images reconstructed from the same scan data. These improvements in measurement capability may be particularly important in measuring the change in plaque burden over time, and this is an area of extremely active research. Rapid progression of coronary atherosclerosis and thus potentially calcified plaque may be a key predictor of future clinical events.

STANDARDIZED SCANNING PROTOCOL FOR MDCT The continued technological change in MDCT makes standardization problematic. For measuring CAC, by far the greatest experience is using prospective ECG gating (also called triggering) and scanning in a sequential scan mode. Gantry speeds of 0.5 s or greater should be used for cardiac applications. 120 kVp with mAs ranging from 50 to 100 are consistently used in research and clinical applications. The tradeoff between 50 and 100 mAs is between dose (effective dose ranges between 1 and 2 mSv, respectively) and image noise. Note that increasing mAs with patient size is desirable to maintain image quality. In the MESA CT protocol, mA was increased by 25% for those individuals weighing greater than 100 kg (220 lb). Slice collimation is relatively standardized at 2.5 mm for MDCT systems when operating in the sequential mode. MDCT scans should be performed at the maximum multislice capability (i.e., widest nominal beam width) possible in order to reduce variability related to coronary and

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Fig. 2. Improvement in spatial resolution using 1.25-mm slice collimation. Images A and B are from the same cardiac-gated scan through the heart performed on a multidetector-row CT(16) system (General Electric LightSpeed Pro) using 0.4-s gantry rotation and segmented reconstruction algorithm. (A) The direct axial slice reconstructed with 2.5-mm slice thickness; (B) the same data reconstructed at 1.25-mm slice thickness. Note how there is increased image noise apparent in the 1.25 slice by the more “textured” appearance of the homogenous blood in the ascending aorta and main pulmonary artery. (C,D) Oblique reconstructions positioned to create a cross-section through the left anterior descending coronary artery using the 2.5-mm and 1.25-mm data respectively. Note how the calcifications in the wall of the left anterior descending artery demonstrate more detail secondary to the improved spatial resolution with the 1.25-mm dataset. These sets of images demonstrate how improved technique will be required as slice thickness is reduced if the level of noise is to remain constant.

patient motion. The wider beam will also reduce extraneous scatter radiation and increase dose efficiency while reducing patient exposure.

CALIBRATED CALCIUM MASS Calibration of any measurement device is central to improving accuracy. The Agatston score is a quantitative scoring system with limitations related to the discrete weighting factors that increase variability, and it has no straightforward means of calibration (41,51,52). The various volume-scoring methods allow calculation of the volume of calcified plaque in S.I. units such as milliliters. Volume methods are strongly influenced by the threshold of “CT measurable calcium,” typically set at 130 HU. It has already been demonstrated that there is variability between patient and CT system in the determination of this threshold (27). Plaque volume does not account for plaque

density, which may provide important information in relationship to CVD risk assessment. There are several methods of determining a calibrated mass, which include calibrating the CT scanner to an external standard as well as including a calibration phantom within the scan field of view for each scan (Fig. 3). The calibrated calcium mass in milligrams has several advantages. Based on imaging principles, it is more robust to the effect of partial volume averaging than either a volume score or Agatston score. Data with MDCT in both phantom studies and with human research participants have demonstrated less variability with a calibrated mass measurement than either volume or Agatston methods (41,52). Lastly, the calibrated mass can be reported in milligrams of calcium and will allow for standardization of measurements across CT systems and techniques as well as for currently undiscovered future techniques.

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Fig. 3. Calibration phantom for calcium mass. One slice from a research study in which a calcium calibration phantom is used. These phantoms were originally designed for measurement of trabecular bone mineral density with CT, also known as quantitative computed tomography (QCT). The phantom is positioned underneath the participant during the scan and contains four cylinders with the following concentrations of calcium hydroxyapatite: 0 mg/mL, 50 mg/mL, 100 mg/mL, and 200 mg/mL. These known quantities of calcium are then used to calibrate the CT numbers such that the resulting mass determination is reported in mg of calcium hydoxyapatite. Calibration of each patient’s scan provides the greatest gain in accuracy.

STUDIES IMPACTING THE CLINICAL APPLICATION OF CAC Increasing evidence supports the use of CAC as a tool for better quantifying coronary heart disease risk among asymptomatic individuals. The Saint Francis Heart Study has recently reported data with 4.3 yr on average of follow-up of asymptomatic individuals aged 50–70 yr using EBCT (53). In this study, participants with CAC scores >100 had a 10-fold increase in relative risk for CVD events. The calcium score had significantly better prognostic ability for coronary events than the Framingham Risk Index. The National Heart, Lung and Blood Institute’s MESA is following an asymptomatic cohort of 6800

individuals whose coronary calcium was measured by either EBCT or MDCT between 2000 and 2002 (39). The results from MESA will provide data on both prevalence and the predictive ability of CAC for CVD events in men and women as well as four ethnic groups.

CONCLUSION Accumulating evidence supports the use of the calcified plaque as measured by cardiac CT (EBCT or MDCT) as a valuable predictor of future CVD risk. Ongoing population-based research and clinical trials will provide additional information to determine the appropriate clinical role. Calibration of car-

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diac CT measurements of coronary calcified plaque burden to mass of calcium will improve accuracy and reduce variability. As both EBCT and MDCT systems continue to improve in terms of image quality, tracking the progression of plaque burden and greater understanding of calcified plaque morphology will provide important new information on coronary heart disease. Based on preliminary data, it is likely that coronary calcium provides additive information to traditional CVD risk factors. The specific results of ongoing epidemiological studies will help determine the appropriate at-risk population for CVD screening with cardiac CT for coronary calcium. Cardiac CT with MDCT is well positioned to make screening for subclinical coronary atherosclerosis a viable and cost-effective option for identifying the individual at elevated CVD risk. Once these individuals are identified, proven interventions for CVD prevention are currently available and can be employed to reduce the tremendous burden of CVD on the population.

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44. Kachelriess M, Sennst DA, Maxlmoser W, Kalender WA. Kymogram detection and kymogram-correlated image reconstruction from subsecond spiral computed tomography scans of the heart. Med Phys 2002;29:1489–1503. 45. Kopp AF, Ohnesorge B, Becker C, et al. Reproducibility and accuracy of coronary calcium measurements with multi-detector row versus electron-beam CT. Radiology 2002; 225:113–119. 46. Hong C, Becker CR, Schoepf UJ, Ohnesorge B, Bruening R, Reiser MF. Coronary artery calcium: absolute quantification in nonenhanced and contrast-enhanced multi-detector row CT studies. Radiology 2002;223:474–480. 47. Ohnesorge B, Becker C, Flohr T, et al. Coronary calcium scoring with electrocardiographically pulsed multislice spiral computed tomography and reduced radiation exposure. Am J Cardiol 2001;88:82E. 48. Jakobs TF, Becker CR, Ohnesorge B, et al. Multislice helical CT of the heart with retrospective ECG gating: reduction of radiation exposure by ECG-controlled tube current modulation. Eur Radiol 2002;12:1081–1086. 49. Jakobs TF, Wintersperger BJ, Herzog P, et al. Ultra-low-dose coronary artery calcium screening using multislice CT with retrospective ECG gating. Eur Radiol 2003;13:1923–1930. 50. Strong JP. Natural history and risk factors for early human atherogenesis. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Clin Chem 1995;41:134–138. 51. Callister TQ, Cooil B, Raya SP, Lippolis NJ, Russo DJ, Raggi P. Coronary artery disease: improved reproducibility of calcium scoring with an electron-beam CT volumetric method. Radiology 1998;208:807–814. 52. Ferencik M, Ferullo A, Achenbach S, et al. Coronary calcium quantification using various calibration phantoms and scoring thresholds. Invest Radiol 2003;38:559–566. 53. Arad Y, Roth M, Newstein D, Guerci AD. Heart Scan May Be Better Than Standard Risk Factors at Estimating Heart Disease Risk, American College of Cardiology 52nd Annual Scientific Session, Chicago, Ill, 2003.

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Coronary Calcium Scoring With Multidetector-Row CT Rationale and Scoring Techniques ROMAN FISCHBACH, MD AND DAVID MAINTZ, MD

INTRODUCTION Coronary heart disease is the leading cause of death, illness, and disability in populations worldwide. Strategies to reduce the risk of coronary heart disease include the early initiation of primary preventive measures including lifestyle changes and/ or medical therapy in patients with subclinical disease. The reliable identification of presymptomatic patients, however, is problematic by conventional risk assessment based on traditional risk factors. Direct visualization and quantification of the coronary atherosclerotic plaque burden would be desirable to more precisely determine a patient’s coronary heart risk. In recent years, there has been an important increase of interest in the use of noninvasive measurement of coronary arterial calcification as a screening test for coronary atherosclerosis. Since coronary artery calcification is conceived as a manifestation of atherosclerosis in the arterial wall, the detection of coronary calcifications may serve as a marker for the presence of coronary artery disease. The most frequent application of coronary calcium scoring has thus become the assessment of an individual’s future risk for a myocardial event. This indication and the predictive value of coronary artery calcium measurement and its role in the assessment of myocardial event risk has always been a matter of debate. Until the introduction of subsecond mechanical computed tomography (CT) scanners, coronary calcium measurement remained a domain of electron beam CT (EBCT). Owing to the limited number of EBCT scanners available in dedicated imaging centers, access to coronary CT scanning has long been restricted. On the other hand, the scan protocol and the quantification method remained quite uniform for a decade. Many of the whole-body multidetector-row CT (MDCT) systems installed today are equipped with the necessary hard- and software to perform examinations of the heart using either prospective triggering of sequential scans or retrospective gating of spiral CT scans. This development opens CT scanning of the heart for a larger patient population. Parallel to the introduction of a growing range of MDCT systems capable of performing electrocardiogram (ECG)-synchronized cardiac scans, differFrom: Contemporary Cardiology: CT of the Heart: Principles and Applications Edited by: U. Joseph Schoepf © Humana Press, Inc., Totowa, NJ

ent scan protocols have been suggested and new approaches for the quantification of coronary artery calcifications have been introduced. Today no accepted standards exist for performing MDCT studies for quantification of coronary artery calcifications. This chapter will give an overview of the basic concepts of imaging of coronary artery calcification and will review current techniques and indications for the “calcium scoring” examination, with special regard to MDCT technique.

CORONARY HEART DISEASE Cardiovascular disease has been the leading cause of death in the United States ever since 1900, with the exception of the influenza epidemic in 1918. Although remarkable advances have been made in prevention and treatment of coronary heart disease, it remains the major cause of mortality and morbidity in the industrialized nations and accounts for 54% of all cardiovascular deaths and 22% of all deaths in the United States (1). From 1990 to 2000, the death rate from coronary heart disease declined 25%, but the absolute number of deaths decreased only 7.6%. Coronary heart disease typically manifests in middle-aged and older, predominantly male, individuals. The average age of a person having a first myocardial infarction is 65 yr in males and 70 yr in women. In up to 50% of coronary heart disease victims, sudden coronary death or nonfatal myocardial infarction is the first manifestation of disease, and approx 50% of patients with acute myocardial infarction die within the first month of the event (2,3). The identification of asymptomatic persons with subclinical disease who are at high risk of developing a future coronary event and who could potentially benefit from preventive efforts thus is of major economic and clinical importance. Coronary heart disease is the product and manifestation (myocardial infarction, stable and unstable angina, and myocardial dysfunction) of coronary artery disease (CAD), in the form of coronary atherosclerosis. Traditionally, coronary heart disease risk stratification has been based on well-known clinical and biochemical factors. Moderately effective preventive treatment is available: lipid lowering with HMG-CoA reductase inhibitors (statins) or antiplatelet therapy (aspirin) have both resulted in decreased incidence rates of coronary events (4,5). Coronary heart disease thus seems to be a suitable target for screening efforts. However, many myocardial events are not accounted for by these risk factors alone. Therefore efforts have been made

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to develop new diagnostic modalities that may provide an improved approach to coronary heart disease risk assessment.

CORONARY ARTERY CALCIFICATION Autopsy studies have shown that coronary artery calcification is an excellent marker of CAD (6,7). Histomorphological evaluation of coronary arteries at autopsy has produced good correlation between coronary artery calcification and overall plaque burden (8–10), but it is not known whether the amount of calcium reflects the amount of total plaque over time or after therapeutic intervention. Calcification seems to be a better marker for overall coronary plaque burden than individual stenosis based on residual lumen size (9). Calcifications are frequently present long before clinical manifestation of atherosclerotic disease. Although coronary artery calcification is found more frequently in advanced lesions, it may be histologically identified early in the disease process and has been detected in lesions that are seen as early as the second decade of life. On the other hand, atherosclerotic plaque can be present when coronary calcium is either absent or not detectable by CT, even though histopathologic studies confirmed an intimate relation between coronary atherosclerotic plaque area and coronary calcium area. PATHOPHYSIOLOGY OF CORONARY ARTERY CALCIFICATION

The development of coronary atherosclerosis can be described as a sequence of changes in the arterial wall. An in-depth description of the pathophysiology would be beyond the scope of this work, and the interested reader is referred to the literature (11–13). Initial lesions seem to occur secondary to an injury of the coronary artery endothelium. Circulating histiocytes traverse the injured vascular endothelium and gather in the arterial wall. These histiocytes transform into macrophages and can accumulate lipid. Lipid accumulation can be identified as fatty streaks, the initial and intermediate lesions in atherosclerotic plaque formation. Histologically, different types of atherosclerotic lesions can be distinguished, which has led to a classification system suggested by the American Heart Association. Lesions are designated by Roman numerals I through VI (see Fig. 1). Initial and intermediate lesions are types I, II, and III. The advanced atherosclerotic lesions are subdivided into lesions type IV, V, and VI. The type IV lesion (atheroma) is characterized by extracellular intimal lipid accumulation, the lipid core. The type V lesion contains fibrous connective tissue formations. If parts of the lesion are calcified, it becomes a Vb lesion. If the lipid core is absent, the type Va or Vb lesion is classified as type Vc. Type IV and type V lesions may develop fissures, hematoma, and/or thrombus (type VI lesion). Although this classification system suggests a linear sequence of events, plaque development seems to be more complex (13). This is suggested by angiographic studies, which have shown that rapid progression of minor lesions to high-grade stenosis may occur in only a few months (14,15). PLAQUE MORPHOLOGY AND DEGREE OF CALCIFICATION

Apatite in the form of {Ca [Ca3 (PO4)2] 3}2+× 2 OH– (hydroxyapatite) and carbonate apatite is the predominant mineral

Fig. 1. Sequence of atherosclerotic lesions according to the classification system by the American Heart Association and the American College of Cardiology. The early lesion is characterized by isolated macrophage foam cells (type I lesion) or mainly intracellular lipid accumulation (type II). Type II changes and early extracellular lipid pools characterize the intermediate lesion. The more advanced lesions contain a core of extracellular lipids (atheroma, type IV), or multiple lipid cores and fibrotic layers or calcifications (type V). A lesion with a surface defect and associated thrombus or hematoma is the “complicated” type VI lesion. Diagram modified according to (11).

form in calcified lesions. Atherosclerotic calcification is an organized, regulated process (similar to bone formation) that occurs only when other aspects of atherosclerosis are also present. Nonhepatic Gla-containing proteins like osteocalcin, which are actively involved in the transport of calcium out of vessel walls, are suspected to have key roles in the pathogenesis of coronary calcification. Osteopontin and its mRNA, known to be involved in bone mineralization, and mRNA for bone morphogenetic protein-2a, a potent factor for osteoblastic differentiation, have been identified in calcified atherosclerotic lesions. Although the process of calcium accumulation in atherosclerotic lesions is not fully understood, it seems to be an active process, which involves mechanisms similar to bone formation and resorption (16–18). Regardless of the mechanisms involved, it is evident that calcium is very common in advanced atherosclerotic lesions. Histologically, coronary artery plaque can be also classified as plaque rupture, plaque erosion, vulnerable plaque, fibroatheroma, fibrous plaque, plaque hemorrhage, and healed plaque rupture. Rupture is characterized by an acute luminal thrombus with connection to a plaque with a lipid-rich core. Plaque erosion represents a plaque with an intact fibrous cap

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Table 1 Prevalence of Coronary Artery Calcification Detected by CT in Asymptomatic Men and Women (adapted from ref. 22) Asymptomatic Age

Men (%)

Women (%)

–29 30–39 40–49 50–59 60–69 70–79 80–89

11 21 44 72 85 94 100

6 11 23 35 67 89 100

and acute luminal thrombus. The “vulnerable plaque” or thinned-cap fibroatheroma shows a plaque with a thin fibrous cap and infiltration of macrophages. The pattern of calcification was correlated with the plaque morphology in a histomorphologic study of patients dying suddenly with severe coronary disease (19). The greatest amount of calcium was found in healed ruptures, followed by fibroatheroma. Acute plaque ruptures were most frequently seen in segments with speckled or no calcification, but did also occur in areas with diffuse calcifications. From these observations it can be assumed that calcification reflects healing of plaque rupture and intraplaque hemorrhage as well as a response to inflammation in the plaque. Calcification may thus be seen as an attempt of the arterial wall to stabilize itself, since calcified and fibrotic plaques are much stiffer than lipid-rich lesion. The earlier concepts suggesting that calcification is associated with plaque instability are not supported by recent data. In a study of 40 patients with acute coronary syndromes and no or moderate angiographic coronary disease, 36% of culprit lesions were not calcified (20). Because most acute ruptures seem to occur in areas with only little calcification, it is questionable whether coronary calcification could be a marker for plaque instability. Furthermore, we will have to accept that calcification pattern is not helpful in localizing potentially vulnerable lesions, as it has been shown that unstable plaque can be present in vessels with a wide range of calcification patterns as well as in vascular segments without detectable calcium deposits. Even if the individual calcification or calcified plaque does not equal a possible future culprit lesion, the presence and extent of coronary artery calcifications reflect the total plaque burden, and as such the likelihood of the presence of potentially vulnerable lesions. Using this concept, the demonstration of coronary artery calcium accumulation identifies the patient with coronary artery disease, and the degree of calcification can be considered a potential risk factor (21). PREVALENCE OF CORONARY ARTERY CALCIFICATION

The prevalence of coronary artery calcification in asymptomatic as well as symptomatic persons is well studied. Table 1 shows data from an early study investigating the prevalence of coronary artery calcification in asymptomatic men and women of various ages (22). The prevalence in men is evidently higher

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than the prevalence in women well into the postmenopausal period, and it is obvious that the prevalence is age dependent. Several investigators have since reported coronary calcium scores in large asymptomatic populations (see Fig. 2). The calcium score distributions published for these asymptomatic mainly white American populations can be used to classify patients compared with the expected norm. All investigators (23–25) report a steep increase in coronary calcium score with age: the 75th percentile ranges between 36 and 44 for males aged 45–50 yr, between 101 and 116 for males aged 50–55 yr, and between 410 and 434 for males aged 60–65 yr. Interestingly, the absolute calcium scores are quite similar in the different US populations studied. Even though there is a positive association of the amount of coronary artery calcium and age, coronary artery calcification is not an inevitable aspect of aging. In older adults with minimal clinical cardiovascular disease, 16% of the individuals examined had no detectable coronary artery calcifications (26).

IMAGING OF CORONARY ARTERY CALCIFICATION Calcium strongly attenuates X-rays as a result of its relatively high atomic number; therefore, a variety of radiological imaging techniques, including chest X-ray, fluoroscopy, EBCT, conventional, spiral, and MDCT are suitable methods for detecting coronary calcifications. CONVENTIONAL X-RAY TECHNIQUES

The chest film has the least sensitivity, and only extensive calcifications can be identified (27). Fluoroscopy has a much higher sensitivity compared to plain chest radiography, but characterization, quantification, and documentation are problematic using a projection technique. Furthermore, fluoroscopy requires a skilled and experienced examiner. Nevertheless, fluoroscopically detected calcifications were shown to carry significant prognostic information. A prospective study using fluoroscopy in high-risk asymptomatic populations found that individuals with detectable coronary calcifications were three times as likely to develop angina or to experience myocardial infarction or death than persons without coronary calcifications (28). Margolis et al. assessed the significance of coronary artery calcification in 800 symptomatic patients who underwent cardiac fluoroscopy. Calcification was shown by fluoroscopy in 250 patients, of whom 236 (94%) had greater than or equal to 75% stenosis of one or more major coronary arteries at angiography. The 5-yr survival for patients with coronary artery calcifications was 58%, compared with 87% in patients without coronary artery calcifications. The prognostic significance of coronary artery calcification was independent of sex, status of the coronary vessels at angiography, left-ventricular function, or results of exercise tests (29). CT IMAGING TECHNIQUES

Because of the high attenuation of calcium, CT is extremely sensitive in depicting vascular calcifications (Fig. 3). Conventional single-section imaging with acquisition times in the range of 2–5 s allowed identification of coronary artery calcifications, but calcifications are blurred because of cardiac motion, and small lesions may not be detected. Despite these drawbacks, conventional CT seems to be more sensitive in detecting calcifications than fluoroscopy (30). Still, motion artifacts and

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Fig. 2. Coronary artery calcium score in asymptomatic populations. Age- and gender-adjusted 75th percentile of coronary artery calcium in asymptomatic male patient populations reported by (24), (23), and (25). All investigators found a remarkable increase of calcium scores with age. The reported 75th percentile calcium score is quite similar in the different groups.

Fig. 3. Maximum-intensity projection image of a multidetector-row CT coronary scan depicting severely calcified coronary arteries. The right coronary artery (RCA), the left anterior descending artery (LAD), and the left circumflex (lCx) show diffuse calcifications. Small calcium accumulations are seen in the wall of the ascending (arrow) and descending aorta (arrow head).

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Table 2 Results of Reproducibility Measurements Using Electron Beam CT Author (reference) Kajinami et al., 1993 (79) Shields et al., 1995 (80) Wang et al., 1996 (81) Yoon et al., 1997 (82) Callister et al., 1998 (39) Devries et al., 1995 (83) Achenbach et al., 2001 (47) Mao et al., 2001 (43) a Triggering

Patients

Calcium score variability (%)

25 50 72 50 52 91 120 60 57

34 38 29 37 19 49 19.9 24 15a

Volume score variability (%)

28.2 18 16.2

of the scan at 40% RR interval.

resulting volume averaging and breathing misregistration due to different inspiration depth precluded exact calcium quantification. Electron Beam CT

The introduction of EBCT in the mid-1980s made quantification of coronary artery calcifications feasible. The first reports on EBCT to quantify coronary artery calcifications were published in the late 1980s (31,32). EBCT was shown to be much more sensitive than fluoroscopy to detect small and less densely calcified plaque. Only 52% of calcifications detected by EBCT had been detected by fluoroscopy in the study by Agatston and coworkers. EBCT uses an electron beam to sweep stationary tungsten target rings to generate images. A typical scan protocol for coronary calcium detection consists of contiguous 3-mm sections covering the heart with 100-ms exposure time per slice. The scans are prospectively triggered from the electrocardiogram (ECG) of the patient, usually at 80% of the RR interval. The examination is performed during one or two breath-holds. Using EBCT with ECG triggering allowed investigators for the first time to obtain cross-sectional images of the heart with high spatial and temporal resolution. The current is currently limited to 630 mAs, which results in image noise, especially in obese patients. Signal-to-noise ratio, however, is critical for distinguishing small calcifications from image noise. EBCT-based calcium quantification has been criticized for its rather high variability in measurement results. Interscan variability may hamper accurate serial measurements in follow-up studies. The reported mean percentage variability for the calcium score in repeat examinations ranges between 15% and 49% (see Table 2). This variability is well within the reported annual calcium progression rate, rendering interpretation of yearly follow-up examinations difficult. Major reasons for this variability are artifacts resulting from either cardiac motion in scan misregistration or patient motion occurring during the long breath-hold times. The most important factor, however, seems to be the quantification method (see below) and the rather thick section thickness, which renders the measurement susceptible to partial-volume effects. Multidetector-Row CT

The development of subsecond rotation speeds in mechanical scanners in conjunction with the development of partial

scan reconstruction algorithms provided a significant improvement in temporal resolution. Limited volume coverage and slow scan speed were major drawbacks of single-section CT. In comparisons of EBCT and ECG-controlled sequential CT scanning (33,34), the variability between the two modalities was rather poor (42–84%). In combination with ECG-based synchronization of image reconstruction from subsecond singlesection spiral CT, agreement in the classification of subjects as “healthy” or “diseased” based on calcium score categories was above 90% (35). The now widely available MDCT scanners offer the possibility of cardiac imaging with similar or even better image quality than EBCT. This is mainly a result of advantages of acquisition geometry, adjustable tube current, and the possibility of continuous spiral scanning. Four-slice CT systems were introduced in 1998. These systems achieved rotation times as fast as 500 ms, resulting in a temporal resolution of a partial scan of 250 ms for a prospective triggering technique. Latest generation systems offer rotation times of down to 370 ms and can acquire up to 16 slices with nearly isotropic resolution. Despite the fast technological development in MDCT systems, these systems still have a potential disadvantage of inferior temporal resolution compared to a 100-ms exposure time by EBCT. Motion artifacts, especially in the rapidly moving right coronary artery, become increasingly problematic with higher heart rates or cardiac contractility. However, the tube current can be adjusted to improve the signal to noise ratio considerably, which helps to distinguish small calcifications from image noise (36). Extensive validation studies to determine the equivalence of EBCT and MDCT have not been performed. Initial experiences show good correlation of EBCT measurement and prospectively triggered MDCT. A recent study compared different quantification methods and found volume and mass indexes to be superior to the traditional calcium score for comparing the results of EBCT and MDCT, and for determining significant coronary artery disease (37).

QUANTIFICATION OF CORONARY ARTERY CALCIFICATION CT allows for reliable measurements of lesion area and lesion attenuation. On the basis of these measurements quanti-

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Fig. 4. Calculation of the calcium score and effect of partial volumes. This figure illustrates the calcium quantification using the calcium score. The grid represents the pixel matrix. A vessel is depicted containing three oval calcified lesions (white). The perivascular fat (dark grey) has negative CT numbers. The CT number for pixels representing the calcified lesions is given. Every pixel with a CT number above 130 is registered as calcified. The measured CT number in pixels that contain calcified plaque and perivascular fat or vascular structures are an average of the underlying tissues and are scored as calcium containing plaque (speckled pattern) only if the CT number exceeds the threshold of 130 HU. In (A) the left lesion contains 11 pixels with CT numbers greater than 130. The greatest CT number is 289, the lesion score is 11 × 2. The small lesion is scored as 2 × 2, and the plaque on the right contains 8 registered pixels with a peak density of 299 HU, resulting in a lesion score of 8 × 2. The vessel score in this case would be 22 + 4 + 16 = 42. In (B) the same vessel is depicted with a slight change in the position of vessel regarding the pixel matrix. This change in position results in important changes in registered CT numbers. The first lesion now scores as 11 × 4, the small lesion has only one registered pixel, the right lesion is counted as 11 × 3. The vessel score in this case would be 44 + 1 + 33 = 78.

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fication of coronary artery calcifications can be performed using calcium area, calcium score based on area, and plaque density or volume, as well as mass measurement. TRADITIONAL CALCIUM SCORE

The initial quantification method introduced by Agatston et al. used electron-beam tomography for the quantification of coronary calcification and introduced a method for coronary artery calcification quantification, which has since been referred to as the “Agatston score” or calcium score. The Agatston score in its original form is assessed from 20 contiguous 3-mm sections of the heart. A threshold of 130 Hounsfield Units (HU) is empirically set to identify calcifications. This threshold was introduced to exclude noise from the evaluation, since it was more than two standard deviations of the average attenuation of the aorta. In its original form, only plaques related to the coronary arteries with a minimum lesion size of 1 mm2 or two adjacent pixels are included in the calculation, to exclude random image noise. The analysis software will highlight any lesion that contains the minimum number of pixels with more than 130 HU. The observer has to identify scoreable coronary artery lesions, and assigns each lesion to the left main coronary artery, the left anterior descending artery, the left circumflex, or the right coronary artery. A region of interest is placed around each lesion and area, and maximum CT number of each lesion is determined. The calcium score is then calculated by multiplying the individual lesion area with a weighting factor. The maximum CT number per lesion determines this weighting factor. The factor is 1 for a peak lesion attenuation of 130–199 HU, 2 for 200–299 HU, 3 for 300–399 HU, and 4 for a lesion with a density equal to or greater than 400 HU. The sum of all lesion scores is the vessel score, and all vessel scores are summed to calculate the total calcium score. The use of a density-dependent weighting factor makes the area-based Agatston score nonlinear and can mean a dramatic change in the lesion and overall score based on just a single pixel. Only slight changes in the position of a lesion in the measured section, as in repeat examinations, can induce significant changes in the number of registered pixels and the calcium score of a given lesion. Fig. 4 uses an example to illustrate how differences in pixel attenuation of the same lesion from partial-volume effect can influence score results. Problems Using the Calcium Score in MDCT

When applying the Agatston method to coronary calcium scanning based on MDCT technology, it has to be kept in mind that the Agatston score was initially designed for a special protocol and modality (EBCT). Any changes in image acquisition parameters, such as scan volume, section thickness, image increment, image reconstruction kernels, and X-ray spectrum, will influence the quantification result. For example, calcium scans with a four-channel MDCT using a 4 × 2.5-mm detector configuration and prospective triggering will produce 2.5-mm sections instead of 3-mm sections, thus giving more images per volume. Consequently, the resulting score would be falsely high, and mathematical operations need to be introduced to correct for this. If MDCT calcium scanning is performed using spiral data acquisition with overlapping image reconstruction, as suggested by some groups,

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the number of sections per volume will further increase. Because the absolute CT number of a calcium deposit will differ with different CT systems and image protocols, not only the measured area but also the maximum CT number and thus the weighting function for the Agatston score will be affected. CALCIUM VOLUME SCORE

The rather poor reproducibility of calcium quantification results with the use of the Agatston score was realized when calcium scoring was employed to follow the progression or possible regression of coronary atherosclerotic plaque. The calcium volume score (CVS) has been introduced to improve the reproducibility of calcium measurements (38,39). The CVS for each lesion is calculated as the number of voxels in the volume data set that belong to the calcification, multiplied by the volume of one voxel. The determination of calcified plaque volume is independent from the section thickness or image overlap used. An increase in the number of sections scored when overlapping image reconstruction is chosen or when smaller slice thickness is generated, is automatically accounted for. Therefore, the comparability between different modalities is improved over the traditional calcium score. The lack of a density-dependent weighting factor further reduces the influence of partial-volume effects. Since the measured volume of a calcification depends on the attenuation of the lesion as well as the threshold used, the CVS does not represent the true volume of the calcification (40). If the traditional threshold 130 HU is employed, the CVS overestimates the volume of very dense calcifications and underestimates the volume of less dense calcifications. Since the tube current used also affects the attenuation of a calcified lesion, and attenuation influences the lesion volume, a measurement which is standardized, reproducible, and independent of scanner hardware as well as image acquisition parameters is desirable, especially in view of the rapidly increasing diversity of the MDCT systems available. CALCIUM MASS

It has been suggested that the most reliable calcium quantification method would be an absolute hydroxyapatite (Ca-HA) mass measurement, which can be performed similar to bone mineral density assessment (40). Ca-HA mass is proportional to the mean CT number of a calcification multiplied by the lesion volume. Because objects that are smaller than the section thickness are displayed with decreased mean CT numbers, Ca-HA mass automatically corrects for linear partial-volume effects. Furthermore, Ca-HA mass has the advantage of representing a real physical measurement, which can be rather reliably obtained regardless of differences in CT systems and scanning protocols when using appropriate calibration. To obtain absolute values for the calcium mass, a calibration measurement of a sufficiently large calcification with known Ca-HA density has to be performed (41,40). The specific calibration factor needs to be determined for all scanners and protocols. Several commercial analysis software packages allow for mass quantification. It can be expected that the need for reproducible quantification results will result in the replacement of the Agatston score by mass measurements. Large-size studies supporting this assumption are still lacking.

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Fig. 5. Retrospective electrocardiogram gating and overlapping image reconstruction yields motion-free high-resolution images, which allow multiplanar reformation showing the heavily calcified right coronary artery (RCA). High-attenuation calcification, intermediate-attenuation vascular and cardiac structures, and the dark perivascular fat are well differentiated.

MDCT EXAMINATION TECHNIQUE Imaging of coronary calcifications is typically performed using a low-dose technique without contrast enhancement. The scan time should be as short as possible to avoid patient motion and breathing artifacts. Synchronization of the image acquisition or image calculation with the cardiac motion is mandatory to scan the heart at reproducible positions to avoid gaps or overlaps, which would result in image misregistration. Therefore, continuous ECG recording is necessary to either trigger image acquisition in sequential scanning or to synchronize the image generation in spiral scans. The best possible temporal resolution is required for motion-free image acquisition. The coronary arteries are easily recognized in their epimyocardial course surrounded by the low-attenuation periarterial fat. Owing to the high density of vascular calcifications, even small calcium deposits are detected with high sensitivity (Fig. 5). The patient is positioned as in any other examination of the thorax. The scan extends form the midlevel of the left pulmonary artery down to the diaphragm, and is planned on a scout image. All MDCT scanners are able to cover this 10- to 15-cm range in one breath-hold. Continuous table feed as in spiral technique allows for somewhat faster volume coverage than sequential, stepwise scanning. In order to keep the scan protocols comparable with the increasing number of scanners and possible image-acquisition parameters, standard parameters for MDCT scanning should be developed. So far no official recommendations exist. A recommendation of image and acquisition and evaluation parameters is given in Table 3. SEQUENTIAL SCANNING

In prospectively triggered sequential scanning, each scan is started at a predefined position in the cardiac cycle. In this approach, the next RR interval is estimated from the previous RR intervals. As long as the heart rate and rhythm remain con-

stant, a prospective estimation of the duration of the next RR interval can be used to reliably position the scan in the mid to late diastole. In patients with change in heart rate during the necessary breath-hold or with arrhythmia, motion artifacts can impose a major problem for reliable calcium quantification (42). In EBCT scanning, most groups use an 80% delay of the RR interval for the scan. Recently, a 40% delay has been recommended to increase the scan reproducibility (43). For sequential MDCT scanning, no systematic evaluations have been performed to determine the optimal timing of scan triggering. As a result of the longer image exposure in MDCT, an earlier trigger time in the RR interval than the 80% commonly used in EBCT seems to be better. In coronary MDCT angiography, initial investigations based on spiral scanning and retrospectively gated image reconstruction have shown a wide variation of optimal reconstruction windows. A reconstruction window of 50–60% yielded the best results in terms of motionfree images (44,45). Since motion-free images are crucial for reliable calcium quantification, a similar timing can be expected to yield favorable results in prospectively triggered MDCT scanning. In our experience, individual test scans at the midcardiac level with 50%, 60%, or 70% RR interval can be used to check for the optimal timing (Fig. 6). The best result can then be used for the entire cardiac scan. SPIRAL SCANNING

Spiral image acquisition has several advantages over sequential scanning. The continuous data acquisition speeds up the scanning process, and images can be reconstructed at any position in the scanned volume. A slow table motion during the spiral data acquisition is necessary to allow for oversampling of spiral scan projections (46). This is necessary to allow consistent retrospective ECG-synchronized selection of data for image reconstruction in a predefined phase of the cardiac cycle. As with prospectively ECG-triggered scanning, a specific

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Table 3 Recommendations for Image Acquisition and Evaluation Parameters for Coronary Calcium Quantification With Multidetector-Row CT Scanners Data acquisition Scan mode Tube voltage (kV) Tube current ECG gating

Breath hold Field of view (cm) Matrix Scan range

Spiral 120 100 Retrospective gating in mid to late diastole, usually 50–60% RR interval; individual selection of reconstruction window with least motion artifacts is suggested Inspiration 22 512 Entire heart from 1 cm below tracheal bifurcation to diaphragm Image reconstruction

Section thickness (mm) Reconstruction increment Filter kernel

3 1.5 Medium smooth Data evaluation

Threshold (HU) Minimal lesion size Motion artifacts Reporting

130 1 pixel Include in region of interest Number of calcified vessels, calcium mass and calcium volume score. The Agatston score cannot be recommended

Fig. 6. Scan in the mid-cardiac level at 50% RR interval (A) and 60% RR interval. Motion artifacts affect the depiction of the right coronary artery (RCA) and the left circumflex (lCx). The LCx is not well delineated from calcifications of the mitral valve, which is better appreciated on the motion-free image obtained at 60% RR interval.

position of the reconstruction window in relation to the R peaks of the recorded ECG trace is chosen. Since image reconstruction is performed retrospectively after the data acquisition, an optimal agreement with the desired phase of cardiac cycle is

assured. The user can perform additional reconstruction, if motion artifacts should occur. Thus misregistration because of changes in heart rate is minimal, and spiral scanning can improve the robustness of image reconstruction in arrhythmia,

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Fig. 7. Spiral scanning with tube output modulation. The tube current is reduced to 20% of the nominal value during the systole and is increased to 100% during mid-diastole. The image reconstruction window is placed within the normal tube output.

assuring a direct relation of the positions of the reconstructed images and heart rate. This renders spiral MDCT more stable in terms of image quality and probably measurement reproducibility than competing sequential scanning techniques. Another important factor is overlapping image reconstruction, which is possible with any desired image increment. The use of overlapping image acquisition had already resulted in improved reproducibility of sequential coronary scans (47). The same effect was shown in an initial study using spiral MDCT and overlapping image increment (48). Overlapping image generation decreases the influence of partial-volume effects and increases the sensitivity for small lesions. The obvious disadvantage of spiral scan technique with highly overlapping pitch is the continuous irradiation of the patient even in cardiac phases that are not used for image reconstruction. Thus the radiation exposure is higher than in sequential scanning. The use of a prospective tube-current modulation can compensate for this disadvantage. In phases of the cardiac cycle that are not important for image reconstruction, the tube current can be drastically reduced, and the nominal tube current is used only during the desired mid-diastolic phase (see Fig. 7). RADIATION EXPOSURE

Calcium measurement is mainly applied to apparently healthy individuals. Therefore, radiation exposure has been a concern all along. The radiation exposure should be kept as low as reasonably achievable. Since image noise is a major concern in differentiating small calcifications from noise, a lower level is defined. If prospective triggering is used for MDCT scanning, the effective dose is approx 1 mSv, which is similar to EBCT (49). MDCT with constant tube output during spiral scanning will almost double the radiation exposure. ECG-con-

trolled tube output modulation can achieve a mean dose reduction of 48% for males and 45% for females (50). Considering the advantages of MDCT spiral scanning regarding reproducibility of calcium measurements, this slightly higher effective dose for spiral data acquisition should be acceptable.

CLINICAL APPLICATIONS OF CORONARY CALCIUM MEASUREMENT Reports on the potential for CT imaging of coronary calcifications to identify patients with coronary heart disease began early, with the papers of Tannenbaum (32) and Agatston et al. (31). In their study, Agatston et al. demonstrated that EBCT was much more sensitive than fluoroscopy in detecting coronary calcifications, and that patients with symptomatic coronary heart disease displayed higher mean calcium scores than asymptomatic subjects (Fig. 8). CORONARY ARTERY CALCIFICATION AND ANGIOGRAPHIC STENOSIS

In the following years, studies were conducted to confirm these initial results and to assess the ability of CT to identify patients with significant coronary artery obstruction. Accuracies for predicting angiographic stenoses were reported by several investigators. Table 4 lists the reported sensitivities and specificities of CT coronary calcium scanning for predicting angiographic stenoses. There is only a moderate correlation between calcification score, as demonstrated by CT, and coronary narrowing, as shown by catheter angiography (51). Positive arterial remodeling may be an explanation for the relative lack of correlation between the degree of calcification and luminal narrowing (52,9). In patients under age 50 yr, the sensitivity of calcification detected by CT is approx 85%, with a specificity of about 45% as compared to coronary angiography

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Fig. 8. Comparison of mean absolute calcium scores in 475 symptomatic patients without and 109 patients with a diagnosis of coronary heart disease. The calcium score increases with patient age, and there is a significant difference between patients with and without coronary heart disease (31). Table 4 Relationship of Coronary Calcium and Obstructive Coronary Artery Disease in Coronary Angiography Author (reference) Breen et al., 1992 (84) Fallavollita et al., 1994 (85) Devries et al., 1995 (83) Rumberger et al., 1995 (86) Budoff et al., 1996 (87) Haberl et al., 2001 (88)

No. of patients

Age (yr)

Sensitivity (%)

Specificity (%)

Positive predictive value (%)

Negative predictive value (%)

100 106 140 139 710 1764

47 44 58 51 56 56

100 85 97 99 95 99

47 45 41 62 44 39

62 66 55 57 72 57

100 70 94 97 84 97

for the detection of significant coronary artery stenosis. In older individuals, the sensitivity of coronary calcification in predicting obstructive CAD is close to 100%, while the specificity remains low owing to the high prevalence of coronary calcium deposits in elderly individuals. The pattern of calcification may be useful in predicting luminal narrowing. The pattern of calcification can be classified as absent, speckled, fragmented, or diffuse (53). Fragmented calcifications represent single linear or wide calcification >2 mm, whereas diffuse calcifications represent segments of continuous calcification >5 mm. Diffuse calcification is more strongly associated with luminal narrowing than speckled calcification (54,55). CORONARY ARTERY CALCIFICATION AND DIFFERENTIAL DIAGNOSIS OF CHEST PAIN

A positive coronary calcium scan has only a low predictive value for identifying stenoses but a concomitant high negative predictive value for ruling out obstructive CAD in the absence of detectable calcifications. It has therefore been sug-

gested to apply calcium scanning to patients with a low to intermediate likelihood of coronary heart disease presenting with chest pain. Even though CT scanning does not allow for assessment of presence and severity of coronary stenoses, the knowledge of the presence or absence of coronary artery calcification can be helpful in making further decisions regarding diagnostic or therapeutic measures. A negative predictive value of 98% has been reported for coronary chest pain or myocardial infarction in subjects with acute symptoms and nonspecific ECG (56). A negative CT calcium scan was furthermore shown to carry prognostic information. In 192 patients observed for a mean of 50 mo, after undergoing an EBCT when presenting to the emergency room because of chest pain, subjects without coronary calcium accumulations had a significantly lower coronary event rate than subjects with a positive CT scan (57). It has to be kept in mind, however, that even though a negative CT scan result for calcium does imply a low likelihood of significant luminal obstruction, the presence of atherosclerotic

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Table 5 Risk Factors for Developing Coronary Heart Disease Causal risk factors

Predisposing risk factors

Conditional risk factors

Hypercholesterolemia Arterial hypertension Cigarette smoking Diabetes mellitus

BMI > 30 kg/m3 Sedentary life style Family history of premature myocardial infarction Male gender Metabolic syndrome Social factors

Triglycerides Lipoprotein (a) Homocystein Fibrinogen Plasminogen acitvator inhibitor C-reactive protein

plaque cannot be excluded. In this context, it has to be stressed that culprit plaque in sudden coronary death may contain only a little calcium and consequently is not reliably identified by CT. CORONARY ARTERY CALCIFICATION AND DISEASE PROGRESSION

Coronary artery calcification constitutes a surrogate of total plaque burden, and plaque burden is closely related to the risk of future myocardial events. The possibility to observe changes in coronary atherosclerotic involvement noninvasively is an appealing concept for assessment of disease progression and efficacy of primary or secondary preventive measures in CAD. Several studies have tracked changes of coronary calcium by EBCT. Score progression seems to be accelerated in patients with obstructive CAD compared with patients who have no clinically manifest disease (27% vs 18%) (58). A mean annual rate of calcium score increase for untreated patients between 24% and 36% has been found. Recent studies have shown the ability of calcium quantification to monitor the progression of coronary calcification and to document the effect of risk-factor modification and medical treatment (38,59,60,61). In 66 patients with coronary calcifications, the observed increase in coronary calcium volume score was 25% without treatment and decreased to 8.8% under treatment with statins (59). It has not been shown whether a decrease in calcium progression also represents a decrease in future event risks. Because multiple trials on lowering cholesterol levels have shown a decrease in mortality, it is plausible that decrease in calcium score progression may be a valuable tool in monitoring and comparing such therapies. If progression is to be assessed in an individual person, a high reliability of the calcium quantification is mandatory. Reported variability from many EBCT studies ranges between 14% and 38%, however, precluding a meaningful interpretation of calcium measurements in the individual patient. MDCT with spiral scanning, overlapping image reconstruction, and use of calcium mass measurement has resulted in a variability of 5% in a first study (48). This study will need confirmation, but a significant improvement for follow-up or therapy control studies may be expected. CORONARY ARTERY CALCIFICATION AND SCREENING FOR CAD Conventional Identification of Subjects at Risk of CAD

According to the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) only 37% of acute

events can potentially be prevented using lipid-lowering therapy as primary prevention in individuals with average cholesterol levels (62). Therefore, risk-assessment tools or screening tests are required that will reliably identify asymptomatic individuals at high risk of hard coronary events to efficiently target therapy. The risk of developing CAD depends on a wide range of environmental and biochemical factors, many of which have been identified in prospective epidemiological studies. Among these well-recognized risk factors are tobacco smoking, high low-density lipoprotein cholesterol levels, low high-density lipoprotein cholesterol, diabetes mellitus, arterial hypertension, and family history of premature myocardial infarction (Table 5). These and other risk factors interact in a complex way, making risk assessment in the individual patient complicated. However, algorithms derived from large prospective epidemiological studies like the Framingham Study (63,64) in the United States and the Prospective Cardiovascular Münster (PROCAM) Study (65) in Germany can be used to calculate a person’s risk of CAD. A person is said to be at increased risk if his or her absolute risk of suffering a future myocardial event within the next 10 yr exceeds 20%. Calculation of an individual’s CAD risk is possible either by using scoring systems and risk charts or computer-assisted algorithms. Subpopulations at a significantly increased global risk of CAD can be identified with a high level of exactness using scores or algorithms for risk assessment. Epidemiological studies have shown that in many individuals without clinically apparent symptoms, the risk of developing a future myocardial infarction may equal or even exceed that of persons with a history of coronary heart disease (65). However, it remains questionable whether the presence of subclinical manifestations of atherosclerosis in these presymptomatic patients can be diagnosed with sufficient certainty based on traditional risk factors alone. Even if standard or traditional risk-factor analysis is quite accurate in identifying populations at risk, exercise stress testing, which is also commonly used to screen for CAD, is characterized by a rather low accuracy in predicting events. The sensitivity of stress testing for identification of asymptomatic middle-aged males at risk for a future myocardial event is less than 40% (66). This is not surprising, since more than twothirds of acute coronary events in previously asymptomatic individuals are due to rupture or erosion of nonobstructive

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Table 6 Coronary Calcium Thresholds and Test Performance for Identifying Subjects With Future Myocardial Infarction or Coronary Death (adapted from Guerci and coworkers [78]) Score

Sensitivity

Specificity

Positive predictive value

Negative predictive value

Overall accuracy

Odds ratio (95% CI)

>80 >160 >600

0.89 0.83 0.55

0.74 0.82 0.94

0.05 0.07 0.13

0.99 0.99 0.98

0.74 0.82 0.94

22.3 (5.1–97.4) 22.2 (6.4–77.4) 20.3 (7.8–53.1)

CI, confidence interval.

coronary plaque (67,13). Nonobstructive CAD seldom causes stress-induced myocardial ischemia, and thus perfusion imaging does not improve the detection rate of subclinical CAD. Coronary Artery Calcification and Predicting Events

The use of noninvasive measurement of coronary artery calcification as a screening test for coronary atherosclerosis has received remarkable interest in recent years and has generated much controversy. Coronary calcium detection by CT makes the assumption that direct demonstration of atherosclerotic vessel-wall involvement in asymptomatic populations with increased coronary heart disease risk is helpful to identify as well as to stratify individuals at risk. To evaluate a possible benefit from CT calcium screening, we first should realize that the main purpose of CAD screening is classification of asymptomatic persons as likely or not likely to have CAD. Early diagnosis of cases with subclinical CAD ought to reduce morbidity and mortality from the specific disease among the population screened, because screening leads to a course of action proven to save lives. If coronary CT screening cannot achieve a significant reduction of morbidity and mortality, it cannot be deemed effective. Therefore, we need to prove that calcium screening of the entire adult population, or even a subpopulation, leads to effective preventive therapy with a substantial benefit, before we can recommend this diagnostic test to healthy individuals and accept the involved expenditure of health care resources. Furthermore, calcium screening should identify high-risk individuals better then traditional riskfactor analysis. In a comparison of persons dying of coronary heart disease and age- and sex-matched individuals dying of other causes, three times as much calcium was found in the coronary heart disease group (68). Coronary calcium was even nine times as abundant in young persons under 50 yr of age dying suddenly, when compared to matched controls dying from accidents (10). Four prospective studies have addressed the prognostic information of coronary calcium scanning in asymptomatic individuals for predicting coronary events (69,70,24,71). Results of these studies are not conclusive, since most of the studies report on a limited number of hard coronary events, the majority of endpoints being revascularizations (possibly triggered by the scan results). Furthermore, some of the studies enrolled self-referred subjects or subjects referred for scanning because of cardiovascular risk factors. Arad et al. reported an odds ratio of 22 for the prediction of myocardial infarction or death in 1173 self-referred men and women, when comparing event rates in the group with calcium

scores greater than 160 vs event rates among subjects with calcium scores less than 160 (see Table 6). The subjects were followed for 3.6 yr, and 18 myocardial infarctions and coronary deaths were registered. The positive predictive value increased as a function of the calcium score, indicating that calcium quantification may be a valid test for vulnerable atherosclerotic plaque. Raggi et al. gave a relative risk of 21 for myocardial infarction or cardiovascular death in subjects with a calcium score greater than the 75th percentile when compared to individuals with a calcium score lower than the 25th percentile (24). While the absolute calcium score had a wide variation in the asymptomatic individuals studied, a calcium score in the upper ageand gender-adjusted quartile seemed to identify subjects at risk better (see Table 7) than an increased absolute calcium score. Twenty-seven events were registered in the 632 subjects during a mean observation of 32 mo. Approximately twothirds of the observed events occurred in patients with mild to moderate amounts of coronary artery calcium (calcium scores below 400). Subjects with massive calcifications (calcium scores >400) represented only 7% of the population scanned and accounted for 22% of all events. On the other hand, 70% of the events observed (19 of 27) occurred in 181 subjects with a calcium score above the 75th percentile adjusted for sex and age. In a study of 926 subjects, who were either referred because of risk factors or self-referred, the highest calcium score quartile was associated with a relative risk of cardiovascular events of 9 compared to subjects without coronary calcification (71). A limitation of this investigation is the high number of revascularizations (23 of 28 reported events) during a mean follow-up of 3.3 yr after scanning. In the South Bay Heart Watch Study, 29 myocardial infarctions and 17 coronary deaths were reported during 44 mo of follow-up in 1196 asymptomatic high-risk subjects (70). Calcium detection by CT failed to improve the identification of patients at risk compared to traditional risk-factor assessment in this study, which was carried out in a population originally screened by fluoroscopy. O’Malley et al. performed a meta-analysis regarding the literature on using CT calcium to predict future events in asymptomatic adults (72). Their results show that the relative risk of calcification for a myocardial infarct or CAD-related death varies from 1 to 22, with a weighted mean of 4.2. Thus, there is a strong indication that coronary calcium scanning may predict myocardial infarction in asymptomatic populations.

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Table 7 Coronary Calcium Scores and Risk of Myocardial Events (according to Raggi et al. [24]) In 632 asymptomatic persons, 8 fatal and 19 nonfatal myocardial infarcts were observed. The use of adjusted calcium quartiles discriminates better between risk statuses than the use of an absolute calcium score. Absolute calcium scores

Patients Annual event rate

0

1–99

100–400

>400

292 0.11

219 2.1

74 4.1

47 4.8

Age- and gender-adjusted calcium score quartile

Patients Annual event rate

1st

2nd

3rd

4th

351 0.2

351 0.2

100 1.4

181 4.5

The question remains, whether calcium scanning performs better than conventional risk-factor analysis. On the basis of the investigations in asymptomatic persons, some would argue that the demonstration of coronary artery calcium, which means the presence of subclinical CAD, should shift an asymptomatic patient from a primary to a secondary prevention category (73). Even though this seems logical, it has not been proven that a positive or increased calcium score is equivalent to a prior myocardial infarction. Even if an increased calcium score puts a person at increased risk, as several investigations imply, one cannot be sure that any benefit would be reached by therapeutic intervention. It has been suggested that the coronary plaque burden should provide a better indicator of the probability of developing an acute coronary syndrome than a person’s age and could replace age as a risk factor in the Framingham risk scores to improve risk assessment (74). Ongoing Trials

Three prospective epidemiological trials under way will examine this issue. One part of the Prospective Army Coronary Calcium (PACC) study (75) is a prospective cohort study of 2000 participants followed for at least 5 yr to establish the relation between coronary calcification and cardiovascular events in an unselected, “low-risk” Army population. The Multi-Ethnic Study of Atherosclerosis (MESA) will use a cohort of 6500 American adults who will undergo CT scanning and will be followed for coronary events for 7 yr. Another population-based, prospective cohort study was begun in Germany in 2000. The RECALL (Risk Factors, Evaluation of Coronary Calcium and Lifestyle) study is designed to define the relative risk associated with EBCT-derived coronary calcium score for myocardial infarction and cardiac death in 4200 males and females aged 45 to 75 yr in an unselected urban population from the large, heavily industrialized Ruhr area (76). CONCLUSION

Risk-factor assessment and noninvasive imaging of atherosclerosis by CT calcium scanning aim at selecting subjects at a

high risk for a future coronary event. While cardiovascular risk factors have been shown to increase CAD risk 1.5–5 times (77,64), odds ratios for increased coronary calcium detected by CT of 22 are reported. This indicates a strong association between coronary calcification and CAD risk, even though formal proof in prospective population-based studies is still lacking. Because atherogenesis is a dynamic process, which represents the result of a life-long exposure of an individual to a variety of predisposing factors, manifestations of subclinical coronary artery disease, as indicated by a positive CT calcium scan, may point to individuals with an increased future cardiac risk. In this respect, coronary calcium may outperform clinical risk-factor analysis in asymptomatic subjects, since the simple presence of even a combination of risk factors does not mean presence of subclinical CAD. Coronary plaque burden has been shown to be a good predictor for future coronary events in angiographic follow-up studies. Since coronary calcium is a reliable marker for CAD and since the amount of coronary calcium reflects total coronary plaque burden, demonstration of coronary artery calcification may thus be of value in improving risk stratification of asymptomatic populations with moderate to increased global coronary heart risk, or in assessing disease progression. There is no formal proof that coronary heart disease risk can be reduced in patients with elevated coronary calcium scores. Neither is there a consensus in the professional societies on how to use the results of calcium scoring for risk-factor management or therapeutic decisions, or who should undergo CT scanning at all. In groups with intermediate or increased risk, calcium scanning may be of value, but long-term prospective studies will have to decide this issue. MDCT scanning, especially using spiral technique with overlapping slice reconstruction and calcium quantification based on calibrated system and calcium mass measurement, holds promise to develop as the reference in the future.

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64. Wilson PW, D’Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation 1998;97: 1837–1847. 65. Assmann G, Cullen P, Schulte H. Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the prospective cardiovascular Munster (PROCAM) study. Circulation 2002;105:310–315. 66. Detrano RC, Froelicher VF. Exercise testing: uses and limitations considering recent studies. Prog Cardiovasc Dis 1988;31:837–845. 67. Petursson M, Jonmundsson E, Brekkan A, et al. Angiographic predictors of new coronary occlusions. Am Heart J 1995;129: 515–520. 68. Eggen DA, Strong JP, McGill HC. Coronary calcification: Relationship to clinically significant coronary lesions and race, sex and topographic distribution. Circulation 1965;32:948–955. 69. Arad Y, Spadaro LA, Goodman K, et al. Prediction of coronary events with electron beam computed tomography. J Am Coll Cardiol 2000;36:1253–1260. 70. Detrano RC, Wong ND, Doherty TM, et al. Coronary calcium does not accurately predict near-term future coronary events in high-risk adults. Circulation 1999;99:2633–2638. 71. Wong ND, Hsu JC, Detrano RC, et al. Coronary artery calcium evaluation by electron beam computed tomography and its relation to new cardiovascular events. Am J Cardiol 2000;86:495–498. 72. O’Malley PG, Taylor AJ, Jackson JL, et al. Prognostic value of coronary electron-beam computed tomography for coronary heart disease events in asymptomatic populations. Am J Cardiol 2000; 85:945–948. 73. Hecht HS. Impact of plaque imaging by electron beam tomography on the treatment of dyslipidemias. Am J Cardiol 2001;88:406–408. 74. Grundy SM. Coronary plaque as a replacement for age as a risk factor in global risk assessment. Am J Cardiol 2001;88:8E–11E. 75. O’Malley PG, Taylor AJ, Gibbons RV, et al. Rationale and design of the Prospective Army Coronary Calcium (PACC) Study: utility of electron beam computed tomography as a screening test for coronary artery disease and as an intervention for risk factor modification among young, asymptomatic, active-duty United States Army personnel. Am Heart J 1999;137:932–941. 76. Schmermund A, Möhlenkamp S, Stang A, et al. Assessment of clinically silent atherosclerotic disease and established and novel risk factors for predicting myocardial infarction and cardiac death in healthy middle-aged subjects: rationale and design of the Heinz Nixdorf RECALL Study. Risk Factors, Evaluation of Coronary Calcium and Lifestyle. Am Heart J 2002;144:212–218. 77. Chambless LE, Heiss G, Folsom AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987–1993. Am J Epidemiol 1997;146:483–494. 78. Guerci AD, Arad Y. Potential use of Ca++ scanning to determine the need for and intensity of lipid-lowering therapy in asymptomatic adults. Curr Cardiol Rep 2001;3:408–415. 79. Kajinami K, Seki H, Takekoshi N, Mabuchi H. Quantification of coronary artery calcification using ultrafast computed tomography: reproducibility of measurements. Coron Artery Dis 1993;4(12): 1103–1108. 80. Shields JP, Mielke CH, Jr, Rockwood TH, Short RA, Viren FK. Reliability of electron beam computed tomography to detect coronary artery calcification. Am J Card Imaging 1995;9(2):62–66 81. Wang S, Detrano RC, Secci A, et al. Detection of coronary calcification with electron-beam computed tomography: evaluation of interexamination reproducibility and comparison of three imageacquisition protocols. Am Heart J 1996;132(3):550–558. 82. Yoon HC, Greaser LE, 3rd, Mather R, et al. Coronary artery calcium: alternate methods for accurate and reproducible quantitation. Acad Radiol 1997;4(10):666–673. 83. Devries S, Wolfkiel C, Shah V, Chomka E, Rich S. Reproducibility fo the measurement of coronary calcium with ultrafast computed tomography. Am J Cardiol 1995;75(14):973–975. 84. Breen JB, Sheedy PF, Schwartz RS, et al. Coronary artery calcification detected with ultrafast CT as an indication of coronary artery disease. Radiology 1992;185:435–439.

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Noninvasive Quantification of Coronary Calcium Quantification Methods, Scanner Types, Scan Protocols, Accuracy, and Reproducibility STEFAN ULZHEIMER, PhD, KAISS SHANNEIK, MSc, AND WILLI A. KALENDER, PhD

INTRODUCTION Calcium in the form of hydroxyapatite (HA) is regarded as a known marker for the presence of atherosclerotic lesions of the coronary arteries. Several studies have demonstrated that the risk for coronary events is associated and strongly correlated with the amount of coronary calcium (1,2). The absence of coronary calcium does almost certainly imply the absence of coronary artery disease (CAD) (3), which, according to a World Health Report by the World Health Organization (WHO), is the leading cause of mortality in the world, amounting to 13.7%. Calcium strongly attenuates X-rays as a result of its relatively high atomic number. Therefore, X-ray techniques are quite suitable methods to detect and quantify coronary calcifications. In the past, plain chest radiographs and fluoroscopy were used to detect coronary calcifications, but they are both not sensitive enough and could not be used for the quantification of calcium (4). Since its introduction in the late 1980s, electron beam computed tomography (EBCT) has been well established as a noninvasive imaging modality for the quantification of coronary calcium (5) and the effective diagnosis of CAD. In addition, EBCT has offered the potential to image coronary arteries using CT angiography (CTA) for diagnostic and follow-up studies (e.g., detecting and tracking any changes in the observed parameters, such as the progress of the disease or the response to a certain medication). For the first time, these scanners allowed the tomographic depiction of the entire heart volume (about 120 mm) to be imaged during one breath-hold and with high temporal resolution (ⱖ50 ms). For common protocols, the total acquisition time was 100 ms for single axial sections of 3 mm. From: Contemporary Cardiology: CT of the Heart: Principles and Applications Edited by: U. Joseph Schoepf © Humana Press, Inc., Totowa, NJ

Imaging of the heart has some very high demands to any imaging modality. For instance, it is of great importance to have a very high reproducibility when detecting coronary calcifications in order to be able to track the progress of the disease or the effectiveness of a certain medication. Despite its good temporal resolution, EBCT does suffer from a number of drawbacks, such as its restriction to cardiac applications as a result of limited performance in other fields compared to conventional CT scanners. Therefore, conventional CT has tried to challenge EBCT in its domain of cardiac imaging since the first scanners became available. So, while conventional mechanical scanners without any special arrangements to reduce motion artifacts have been used for the quantification of coronary calcium (6–11), much attention has been put to improve cardiac imaging by developing new reconstruction approaches in image acquisition (12). However, owing to restrictions and limitations in image acquisition speed and low volume coverage (single-slice scanners with 0.75-s gantry rotation time), this early generation of scanners has not completely achieved this ambitious goal. It was not until the introduction of multislice computed tomography (MSCT) in 1998, with the acquisition of four slices simultaneously and an increase of the gantry rotation speed (0.5 ms), that several new clinical applications became much more feasible, such as motion artifact-free imaging of the human heart. The complex 3D motion of the heart can cause any single-slice CT scanner, and even the EBCT in a much higher probability, to miss certain calcifications or even to count them more than once. The new mechanical CT scanners do not suffer from this problem, as they offer continuous spiral image data acquisition. Electrocardiogram (ECG)-triggered and ECG-gated reconstruction techniques have helped with new dedicated reconstruction algorithms to obtain a much better temporal resolution of typically 100–250 ms. These scanners also allowed for thinner slices (4 × 1-mm collimation) to be applied,

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Fig. 1. (A) Severe calcifications of the coronary arteries are clearly depicted even in contrast enhanced CT images for CTA studies. Obviously contrast enhanced scan are not the method of choice to detect small amounts of calcium and for exact quantification of calcium. The scan was performed on a Siemens SOMATOM Sensation 16 scanner with a standard cardiac scan protocol with a slice collimation of 12 × 0.75 mm and a rotation time of 0.42 s. (B) shows a volume rendering of the showing the whole extent of the coronary arteries without any interruptions.

and offered excellent, almost isotropic resolution in the visualization of the coronary anatomy, thereby making it more than suitable in detecting CAD in an early stage of development (Fig. 1). In 2001, a new generation of scanners was introduced by various manufacturers (13,14). These scanners offered further improved spatial and temporal resolution, a reduced scanning time because of the faster gantry rotation (down to 0.42 s), and an increased number of simultaneously acquired slices (up to 16 submillimeter slices). Rapid developments in computer and engineering technology have provided an opportunity to explore new clinical applications and to use cardiac CT imaging as a valuable quantification tool in clinical routine. With the advent of these new MSCT scanners, it becomes even more important to develop and establish standardized concepts for quality assurance in order to determine the systems’ performance characteristics. It clearly becomes mandatory to know the errors of the methods applied and to develop tools which allow for calibration and direct comparison of results obtained on arbitrary scanners. Unfortunately, in the case of the quantification of coronary calcium, this crucial task has been neglected. Moreover, as the quantification of coronary calcium with EBCT is still considered by many to be the “gold standard,” the new methods have to be compared to EBCT. Therefore, a phantom that provides an anthropomorphic and reproducible environment has been designed and developed (15,16). The issue of calcium score reproducibility has been addressed by several clinical studies (17–24). One paper determined the reproducibility to be around 30% (25), while another judged the method as being “. . . not sufficiently reproducible

to allow serial quantification of coronary calcium in individual patients over relatively short periods (<2 years)” (24). In order to determine small changes with statistical significance, the standard deviation of the measurement has to be low. In the following sections we will review scoring methods and concepts for quality assurance and standardization in this field.

QUANTIFYING CORONARY CALCIUM THE AGATSTON SCORE

The first group that used EBCT images for the quantification of coronary calcium were Agatston et al. in 1990. They introduced a pseudo-quantitative scoring method—later called Agatston score—which became the traditional scoring method. The Agatston score in its original form (5) is determined from 20 contiguous EBCT slices of the heart (3-mm slice thickness, no interslice gaps, 100-ms data acquisition time per slice and breath-holding). The most cephalad slice is placed at the lower margin of the main pulmonary artery, and image acquisition is triggered at 80% of the simultaneously recorded ECG signal. Calcified lesions are identified by applying a segmentation threshold of 130 Hounsfield units (HU) on each of the 20 images and ignoring structures with sizes below 1 mm2 to exclude noise from evaluation. For each coronary artery i a region of interest (ROI) is placed around each calcified lesion j in each of the 20 images. In a succeeding step, the area Aij of the ROI in mm2 and the maximum CT number CT# max in HU are determined. The Agatston score, Sij of lesion j in coronary artery i is calculated as the product of the area of the lesion Aij with a weighting factor wij that depends on the maximum CT number CT#ijmax in the lesions for each image:

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Fig. 2. Determination of the weighting factor for calculating the Agatston score.

Fig. 3. Evaluation of two measurements of the same small calcification with EBCT. Agatston score TCS, volume score V and calcium mass m are calculated. The Agatston score shows a variability of 150%. For the volume score and the calcium mass the reproducibility errors are much smaller.

Sij = wij · Aij

(1)

with # ijmax

⎧1 if 150 HU = CT < 200 HU ⎪ ⎪⎪2 if 200 HU = CT # ijmax < 300 HU wij = ⎨ max 0 HU ⎪ 3 if 300 HU = CT # ij < 400 ⎪ max ⎪⎩ 4 if 400 HU = CT # ij

(2)

The total calcium score (Stot or TCS) for all lesions in all coronary arteries is determined by summing up the scores of the lesions for all arteries in all images: Stot = ΣijSij = Σijwij · Aij

(3)

In later publications the score for each of the coronary arteries alone was given separately, e.g.,

SLAD = ΣijSLAD,j

(4)

for the left anterior descending artery (LAD). Figure 2 illustrates the determination of the weighting factor w from the maximum CT number in the lesion, which is described mathematically in equation 2. However, it should be noted that there is not a linear relationship when considering the Agatston score because of the definitive weighting factors being used. Figure 3 demonstrates how the Agatston score is calculated for two EBCT scans of one and the same small artificial calcification with a diameter of 2 mm. By considering this example it becomes evident what the drawbacks of this score are (Table 1) and why the Agatston score can show a quite high variability, which in this case is 150%. Noise and motion are the cause for artifacts and result in small differences in images. The strong dependence of the Agatston score on noise results from the fact that it is based on the maximum CT number

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Table 1 Pros and Cons of the Agatston Score Pros

Cons

Has been used for >10 yr, which resulted in an accumulation of a large amount of data Has been shown to correlate with coronary events

Is unnecessarily complex Was created for a special modality and protocol Uses absolute CT numbers that depend upon reconstruction kernel, data corrections, etc. Does not correspond to any physical measure Is not a linear measure—weighting factors are used Because its definition is based on contiguous, nonoverlapping 3-mm slices, an adaptation of the equations must be undertaken for scanners other than electron beam CT Uses maximum CT numbers and is therefore prone to noise and motion Sensitive to noise and artifacts

that can lead to a difference in weighting factors by a factor of up to two. When scoring one and the same data set on different workstations, the probability of getting different Agatston scores is quite high (26,27). The quite complex description of the score makes it difficult to obtain a decisive conclusion, as it leaves in some points room for interpretation, while in others the programmers knowingly have tried to make the score more robust. However, these small differences obtained from the scoring software seem to be negligible, as the definition of the score itself is quite arbitrary and is not based on any physical fundamentals. Besides the already mentioned strong dependence on small variations resulting from noise and motion, there are a number of other factors that have a serious effect on this scoring method. These include its dependence on absolute CT numbers, the number of slices per scan length, and its nonlinearity for increasing amounts of calcium, which is due to its reliance on nonlinear weighting factors. Furthermore, as the score does not correspond to any physical measure, it cannot be easily compared to “true” values for exactly defined calcifications. A large amount of data has accumulated over the years with the use of the Agatston score, and the risk tables derived for coronary events (28) are the only, but of course very important, advantages of this score. Even though the Agatston score shows a number of serious drawbacks and limitations, it has been used extensively in the past years and has established itself as a de facto standard for coronary calcium scoring. Some groups have suggested modifications for the Agatston score in order to improve its reproducibility (29) or sensitivity (7), but all efforts were not rigorous enough and have not resulted in a better standard. Other groups made modifications to their EBCT scan protocols (e.g., different trigger positions than 80%, mean CT numbers instead of maximum CT numbers, or different thresholds were used), to

achieve an increase in reproducibility or sensitivity (29). Therefore, even for EBCT the data acquired during the last 13 yr are not necessarily validated and cannot be considered exactly comparable. Compared to the known high interscan variability of calcium scores of up to 46% for small calcifications determined for EBCT and the Agatston score (21), even conventional approaches without any dedicated improvements for motionartifact reduction yielded similar results. For example, the intermodality variability in a study which compared conventional 0.75-s sequential scans without ECG triggering to EBCT was 42% (6). It is possible to adapt the Agatston score to a certain degree so that other scanners and other protocols yield similar absolute scoring results as EBCT (Fig. 4) if the scan protocols are carefully designed and corrections are applied when calculating the score. Nevertheless, not all effects that influence the Agatston score on different scanners or for different scan protocols can be taken into account. VOLUME SCORES

Recent studies (30) based on estimating the volume of the calcification provide an alternative quantification method for coronary calcium. This scoring method, which can also be applied to EBCT, has become more and more popular as some studies indicate that it is more robust with respect to reproducibility (25). The determination is very similar to the Agatston score. The volume score represents the volume V of the voxels of the calcification that lie above a certain threshold. A ROI is drawn around each calcified lesion, and for each lesion the number of voxels in the volume data set that lie above a certain threshold is multiplied by the volume of one voxel Vij = NVoxel · VVoxel

(5)

The easiest segmentation approach again is to take all voxels above a certain threshold, e.g., again 130 HU.

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Fig. 4. Correlation of Agatston scores determined with two different scanners (EBCT and a conventional 4-slice scanner with prospective triggering). When the scan protocols on scanners other than EBCT are carefully designed and corrections are applied when calculating the Agatston score quite good agreement of scores on different machines can be achieved.

The total volume score is the sum of all individual lesions: Vtot = Σi,jVij Compared to the traditional scoring method—the Agatston score—this scoring method provides a higher reproducibility (30). However, there are also a few disadvantages when using the volume score as a quantification method. For example, it should be noted that when using a relatively large slice thickness for small calcifications that have a high density, or when there is a fixed threshold, this sc